Chartreusin derivatives and salts thereof

ABSTRACT

This invention relates to a novel chartreusin derivative of the general formula (I): ##STR1## and a salt thereof. This chartreusin derivative and a salt thereof have an excellent antitumor activity, which is exhibited even when the site of cancer inoculation and the site of drug administration are different. This invention further relates to a antitumorous composition containing the above-mentioned compound as active ingredient. This invention furthermore relates to a process for producing the above-mentioned chartreusin derivative or salt thereof.

This invention relates to a novel chartreusin derivative, a saltthereof, an antitumorous composition containing the same as activeingredient, a method for therapy of cancer using said compositions, anda process for producing the chartreusin derivative or the salt thereof.

Chartreusin has already been known to have an antitumorous activity. Forexample, in "Cancer Research, Vol. 37, pp. 1666-1672 (1977)", it isreported that chartreusin was effective against P-388 leukemia, L-1210leukemia and B-16 melanoma. However, it is also reported in the samelitereture that this effect was obtained in a system in which cancer wasinoculated intraperitoneally followed by intraperitoneal administrationof the chartreusin, and that chartreusin was not effective at all whenthe site of cancer inoculation and the site of chartreusinadministration were different. Under these circumstances, chartreusinhas not yet been developed.

The present inventors perceived the excellent antitumorous activity ofchartreusin, and have conducted extensive research to allow thechartreusin derivative to always exhibit its excellent activity evenwhen the site of cancer inoculation and the site of administration ofthe chartreusin derivative are different. As a result, the presentinventors have found novel chartreusin derivatives which exhibit anexcellent antitumorous activity even when the site of cancer inoculationand the site of drug administration are different, for example, whencancer is intraperitoneally inoculated and the drug is intravenouslyadministered, or when cancer is subcutaneously inoculated and the drugis intravenously administered.

According to this invention, there is provided a chartreusin derivativeof the general formula (I), or a salt thereof: ##STR2## wherein X₁ is ahydrogen atom or a substituted or unsubstituted C₁₋₃ alkyl group; X₂ isa substituted or unsubstituted C₁₋₃ alkyl group, a substituted orunsubstituted C₁₋₂ alkylcarbonyl-C₁₋₂ alkyl group, a substituted orunsubstituted phenyl group, a substituted or unsubstituted phenyl-C₁₋₂alkyl group, a substituted or unsubstituted furyl group or a substitutedor unsubstituted thienyl group; in the case where X₁ and X₂ are bothsubstituted or unsubstituted alkyl groups at the same time, the totalnumber of carbon atoms of these alkyl groups is 4 or less; in the casewhere X₂ is a substituted or unsubstituted phenyl group, a substitutedor unsubstituted phenyl-C₁₋₂ alkyl group, a substituted or unsubstitutedfuryl group or a substituted or unsubstituted thienyl group X₁ is ahydrogen atom; X₁ and X₂, when taken together with the adjacent carbonatom, may form a substituted or unsubstituted C₃₋₇ cycloalkylidene; andQ is ##STR3## (in these three formulas, each of R, R' and R" is asubstituted or unsubstituted C₁₋₁₁ alkanediyl group, a substituted orunsubstituted C₂₋₁₁ alkenediyl group, a substituted or unsubstitutedC₂₋₁₁ alkynediyl group, a substituted or unsubstituted C₃₋₁₀cycloalkanediyl group, a substituted or unsubstituted C₅₋₁₀cycloalkenediyl group, or a substituted or unsubstituted phenylenegroup; each of Z₁, Z₁ ' and Z₁ " is a hydrogen atom or a substituted orunsubstituted C₁₋₆ alkyl group; and Z₂ is a hydrogen atom, a substitutedor unsubstituted C₁₋₆ alkyl group, a formyl group, a substituted orunsubstituted C₁₋₆ alkylcarbonyl group, a substituted or unsubstitutedbenzoyl group, or a substituted or unsubstituted benzyloxycarbonylgroup; Z₁ and Z₂, when taken together with the nitrogen atom, may form asubstituted or unsubstituted nitrogen-containing C₂₋₁₀ heterocyclicgroup), a substituted or unsubstituted C₁₋₁₁ alkyl group, a substitutedor unsubstituted C₂₋₁₁ alkenyl group, a substituted or unsubstitutedC₃₋₁₁ alkynyl group, a substituted or unsubstituted C₃₋₁₀ cycloalkylgroup, a substituted or unsubstituted C₅₋₁₀ cycloalkenyl group, asubstituted or unsubstituted C₁₋₁₀ alkylcarbonyl group, a substituted orunsubstituted C₁₋₁₀ alkoxycarbonyl group or a substituted orunsubstituted phenyl group, the total number of atoms of Q other thanthe hydrogen atoms being 30 or less.

This invention further provides an antitumorous composition comprising,as the active ingredient, at least one member selected from the groupconsisting of the above-mentioned chartreusin derivatives and saltsthereof, a method for therapy of cancer using the above antitumorouscomposition, and a process for producing the above-mentioned chartreusinderivative or a salt thereof.

The chartreusin derivative having an excellent antitumor activity ofthis invention is required to have a substitutent on the OH group in theaglycone moiety of chartreusin and a substituent on each of the OHgroups in the 3'-position and 4'-position of the saccharide moiety ofchartreusin, and can display no excellent antitumor activity when theylack any one of these substituents. The reason why the term "substitutedor unsubstituted . . . group" is used herein is that the antitumoractivity is substantially determined by said . . . group regardless ofthe substituents. The substituent which said . . . group may have may beany group so long as it is pharmacologically acceptable and can keep theaforesaid chartreusin derivatives chemically stable.

Based on the above findings, as to the term "substituted orunsubstituted" used in the above definitions of X₁, X₂, Q, R, R', R",Z₁, Z₁ ', Z₁ " and Z₂ in the general formula (I), the substitutentswhich these groups may have are described in detail below.

The substituent on the C₁₋₃ alkyl group represented by each of X₁ and X₂is a halogen atom, a C₁₋₂ alkoxy group, a C₁₋₂ alkylthio group, or theline; the substituent on the C₁₋₂ alkylcarbonyl-C₁₋₂ alkyl grouprepresented by X₂ is a halogen atom, or the like; the substituent on thephenyl group, the phenyl-C₁₋₂ alkyl group, the furyl group or thethienyl group represented by X₂ is a halogen atom, a cyano group, anitro group, a C₁₋₃ alkyl group which may be substituted by a halogenatom or the like, a C₁₋₃ alkoxy group which may be substituted by ahalogen atom or the like, a C₁₋₃ alkylthio group which may besubstituted by halogen atom or the like, a C₁₋₃ alkylcarbonyl groupwhich may be substituted by a halogen atom or the like, a C₁₋₃alkoxycarbonyl group which may be substituted by a halogen atom or thelike, or a di-C₁₋₃ alkylamino group which may be substituted by ahalogen atom or the like; and the substitutent on the C₃₋₇cycloalkylydene which X₁ and X₂ form when taken together with theadjacent carbon atom is a halogen atom, a C₁₋₂ alkoxy group, a C₁₋₂alkylthio group, or the like.

The combination of X₁ and X₂ is preferably a combination of X₁ being ahydrogen atom with X₂ being a substituted or unsubstituted phenyl group,a substituted or unsubstituted furyl group, or a substituted orunsubstituted thienyl group; with X₂ being a substituted orunsubstituted phenyl group; or with X₂ being a phenyl group which may besubstituted in the o-position and/or m-position of the benzene nucleus.It is particularly preferred that X₂ is a phenyl group which isoptionally substituted by a fluorine atom in the m-position of thebenzene nucleus.

Next, R, R'and R" in the definition of Q are explained below. Thesubstitued on the C₁₋₁₁ alkanediyl group, the C₂₋₁₁ alkenediyl group,the C₂₋₁₁ alkynediyl group, the C₃₋₁₀ cycloalkanediyl group or the C₅₋₁₀cycloalkenediyl group represented by each of R, R' and R" is a halogenatom; a hydroxyl group; a mercapto group; a C₁₋₆ alkoxy group; a C₁₋₆alkylthio group; a C₁₋₆ alkylsulfinyl group; a C₁₋₆ alkylsulfonyl group;an aminocarbonyl group; a hydroxycarbonyl group; a C₁₋₅ alkoxycarbonylgroup; a phenyl group which is optionally substituted by a halogen atom,a hydroxyl group, a mercapto group, a C₁₋₃ alkoxy group, a C₁₋₃alkylthic group or the like; or a 3-indolyl group which is optionallysubstituted by a halogen atom or the like. The substituent on thephenylene group represented by each of R, R' and R" is a halogen atom, ahydroxyl group, a mercapto group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthiogroup, a C₁₋₆ alkylsulfinyl group, a C₁₋₆ alkylsulfonyl group, anaminocarbonyl group, a hydroxycarbonyl group, a C₁₋₅ alkoxycarbonylgroup or the like.

R, R' and R" are preferably substituted or unsubstituted C₁₋₁₁alkanediyl groups or C₃₋₁₀ cycloalkanediyl groups, more preferablysubstituted or unsubstituted C₁₋₅ alkanediyl groups or C₃₋₆cycloalkanediyl groups, and most preferably substituted or unsubstitutedC₁₋₅ alkanediyl groups.

Further, Z₁, Z₁ ', Z₁ " and Z₂ in the definition of Q are explainedbelow. The substituent on the C₁₋₆ alkyl group represented by each ofZ₁, Z₁ ', Z₁ " and Z₂ is a halogen atom, a hydroxyl group, a mercaptogroup, a C₁₋₃ alkoxy group, a C₁₋₃ alkylthio group or the like. Thesubstituent on the C₁₋₆ alkylcarbonyl group or the benzoyl grouprepresented by Z₂ is a halogen atom, a hydroxyl group, a mercapto group,a C₁₋₃ alkoxy group, a C₁₋₃ alkylthio group or the like. The substituenton the benzyloxycarbonyl group represented by Z₂ is a halogen atom orthe like. The substituent on the nitrogen-containing C₂₋₁₀ heterocyclicgroup which Z₁ and Z₂ form when taken together with the nitrogen atom isa halogen atom, a hydroxyl group, a mercapto group, a C₁₋₃ alkoxy group,a C₁₋₃ alkylthio group or the like. The term "nitrogen-containing C₂₋₁₀heterocyclic group which Z₁ and Z₂ form when taken together with thenitrogen atom" means a heterocyclic group, the ring of which is composedof one nitrogen atom and 2 to 10 carbon atoms, and if necessary, anoxygen atom and/or a sulfur atom, and specific examples thereof includeaziridine (C₂), pyrrolidine (C₄), morpholine (C₄), thiomorpholine (C₄),piperidine (C₅), heptaethyleneimine (C₇), etc.

The total number of atoms of Q other than the hydrogen atoms is usually30 or less, preferably 20 or less, more preferably 15 or less.

The case where Q has neither primary, secondary nor tertiary amino groupis explained below. The substituent on the C₁₋₁₁ alkyl group, the C₂₋₁₁alkenyl group, the C₃₋₁₁ alkynyl group, the C₃₋₁₀ cycloalkyl group, theC₅₋₁₀ cycloalkenyl group, the C₁₋₁₀ alkylcarbonyl group or the C₁₋₁₀alkoxycarbonyl group, represented by Q is a halogen atom, a hydroxygroup, a mercapto group, a cyano group, a nitro group, a C₁₋₆ alkoxygroup, a C₁₋₆ alkylthio group, a C₁₋₆ alkylsulfinyl group, a C₁₋₆alkylsulfonyl group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆ alkoxycarbonylgroup, a phenoxycarbonyl group, a C₁₋₆ alkylcarbonyloxy group, a C₃₋₇cycloalkyl group, a phenyl group, a phenoxy group, a phenylthio group, aphenylsulfinyl group, a phenylsulfonyl group, a benzoyl group, abenzoyloxy group, a benzyloxy group or the like. (The above-mentionedC₁₋₆ alkoxy group, C₁₋₆ alkylthio group, C₁₋₆ alkylsulfinyl group, C₁₋₆alkylsulfonyl group, C₁₋₆ alkylcarbonyl group, C₁₋₆ alkoxycarbonylgroup, phenoxycarbonyl group, C₁₋₆ alkylcarbonyloxy group, C₃₋₇cycloalkyl group, phenyl group, phenoxy group, phenylthio group,phenylsulfinyl group, phenylsulfonyl group, benzoyl group, benzoyloxygroup, benzyloxy group or the like may be further substituted. Thesubstituent is a halogen atom, a hydroxyl group, a mercapto group, aC₁₋₃ alkoxy group, a C₁₋₃ alkylthio group or the like.)

The substituent on the phenyl group represented by Q is a halogen atom,a hydroxy group, a mercapto group, a cyano group, a nitro group, a C₁₋₆alkylsulfinyl group, a C₁₋₆ alkylsulfonyl group, a C₁₋₆ alkyl group, aC₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylcarbonyl group, aC₁₋₆ alkoxycarbonyl group, a C₁₋₆ alkylcarbonyloxy group or the like.(The above-mentioned C₁₋₆ alkyl group, C₁₋₆ -alkoxy group, C₁₋₆alkylthio group, C₁₋₆ alkylcarbonyl group, C₁₋₆ alkoxycarbonyl group,C₁₋₆ alkylcarbonyloxy group or the like may be further substituted. Thesubstituent is a halogen atom, a hydroxyl group, a mercapto group, aC₁₋₃ alkoxy group, a C₁₋₃ alkylthio group or the like.)

In this case, Q is preferably a substituted or unsubstituted C₁₋₁₁ alkylgroup, a substituted or unsubstituted C₂₋₁₁ alkenyl group, a substitutedor unsubstituted C₃₋₁₀ cycloalkyl group or a substituted orunsubstituted phenyl group, more preferably a substituted orunsubstituted C₁₋₁₁ alkyl group, a substituted or unsubstituted C₃₋₁₀cycloalkyl group or a substituted or unsubstituted phenyl group, andmost preferably a substituted or unsubstituted C₁₋₁₁ alkyl group or asubstituted or unsubstituted C₃₋₁₀ cycloalkyl group.

The total number of atoms of Q other than hydrogen atom is usually 30 orless, preferably 20 or less, and more preferably 15 or less.

In the above explanations, the alkyl, alkenyl or alkynyl portion of aradical comprising as a constituent an alkyl group, an alkenyl group, analkynyl group, an alkanediyl group, an alkenediyl group, an alkynediylgroup or a radical thereof may be of either a straight chain or abranched chain. Specific examples of, for instance, the alkyl groupinclude methyl, ethyl, propyl, hexyl, undecyl, etc. Specific examples ofthe cycloalkyl and cycloalkenyl portions of the radical comprising as aconstituent a cycloalkyl group, a cycloalkenyl group, a cycloalkanediylgroup, a cycloalkenediyl group or a radical thereof include cyclopropyl,cyclopentyl, cyclohexanyl, etc. Specific examples of the halogen atominclude fluorine, chlorine, bromine, etc.

The salts of the chartreusin derivatives in this invention arephysiologically acceptable organic or inorganic salts, and include, forexample, formates, acetates, propionates, butyrates, hydrochlorides,sulfates, phosphates, etc.

The chartreusin derivatives of this invention include theirstereoisomers when X₁ and X₂ in the saccharide moiety are different. Forexample, there exist an exo isomer (hereinafter abbreviated as "exoform") in which of the O-substituents X₁ and X₂ in the 3'-position and4'-position of the saccharide moiety of the chartreusin derivative, onewhich has a larger molecular weight is located outside with respect tothe bicyclic ring system composed of a six-menbered ring of fucose and afive-membered ring of acetal; and an endo isomer (hereinafterabbreviated as "endo form") in which this O-substituent is locatedinside the bicyclic ring system. Although both isomers have an excellentantitumor activity, the exo form which displays an antitumor activity ina smaller dose is preferred.

Furthermore, the chartreusin derivatives of this invention havestereoisomers when Q is a C₂₋₁₁ alkenyl group or when R, R' or R" is aC₂₋₁₁ alkenediyl group. In the present specification, for example, whenQ is ##STR4## the case where the ##STR5## group on the left side and themethyl group on the right side are upward (or downward) at the same timeis defined as Zusammen (hereinafter abbreviated as (Z)), while the casewhere one of them is upward and the other is downward is defined asEntgegen (hereinafter abbreviated as (E)).

The compound of this invention can be produced usually by reacting a6-O-substituted chartreusin derivative of the general formula (XII):##STR6## wherein Q has the same meaning as defined above, with adimethoxy compound of the general formula ##STR7## or a ketone compoundof the general formula ##STR8## wherein X₁ and X₂ have the same meaningsas defined above, or reacting a 3', 4'-O-substituted chartreusinderivative of the general formula (IV) ##STR9## wherein X₁ and X₂ havethe same meanings as defined above, with a carboxylic acid derivative ofthe general formula ##STR10## wherein Q has the same meaning as definedabove.

Specifically, the compound of this invention can be produced, forexample, by any of the following processes (A) to (C). ##STR11##

When X₁ and X₂ are different in the compound (IV) and separation of thestereoisomers (diastereomers) is necessary, the following separationstep is additionally carried out:

Separation Step Conventional Separation ##STR12##

In this case, the molecular wiehgt of X₁ is lower than that of X₂.Separation of the exo isomer from a mixture of the exo and endo forms bychemical conversion - selective solvorisys of the endo isomer ##STR13##

In the above synthesis example (Process A), when the compound (IV) hasstereoisomers (diastereomers), the ratio between the exo form (V) andthe endo form (VI) in the compound (IV) can be changed to some extent byselecting the reaction conditions.

For example, in the synthesis of an unsubstituted benzylidene seriescompound (X₁ : hydrogen, X₂ : a phenyl group), the proportion of (V) ishigher when (III-1) is used as a reagent than when (III-2) is used. When(III-2) is used, the proportion of (VI) is improved when the reactiontemperature is lowered.

In the step of column separation of (V) and (VI), the column separationshould be conducted several times because the polarities of (V) and (VI)are similar, but as described in the above example, it is also possibleto obtain (V) alone with a high purity easily by a single columnseparation [separation between (V) and (II)] by subjecting only (VI) toselective solvolysis under weakly acidic conditions to convert (VI) into(II).

When, a group of compounds in which Q in the general formula (I)includes a primary amino group or a secondary amino group, and saltsthereof [hereinafter referred to as (I-1)] are synthesized, thefollowing reduction step is additionally carried out:

Reduction Step ##STR14## wherein (I-2) refers to a group of compounds inwhich Q in the general formula (I) includes an N-carbobenzyloxy group.

When a salt of compound in which Q in the general formula (I) includes atertiary amino group is synthesized, an acid treatment step with anorganic acid or an inorganic acid is additionally carried out

When a group of compounds in which Q in the general formula (I) includesa hydroxyl group (hereinafter referred to as (I-3)) are synthesized, thefollowing reduction step, for example, is additionally carried out:##STR15## wherein (I-4) refers to a group of compounds in which Q in thegeneral formula (I) includes a benzyloxy group.

Process B (Via Monosilyl Form) [First Step]

The same as the first step [(II)→(IV)] of the above Process A. ##STR16##

When separation of the stereoisomers (diastereomers) is necessary in thecompound (I), the separation step in the first step of theabove-mentioned Process A is additionally carried out. If necessary, thereduction step in the second step of Process A is also additionallycarried out.

Process C (Via Disilyl Form) [First Step]

The same as the first step [(II)→(IV)] of the above Process A. ##STR17##

[Third Step]

((XIV) is synthesized by any of the following Methods a to d) ##STR18##

[Fifth Step]

The same as the fifth step [(XII)→(I)] of the above Process B.

When separation of the stereoisomers (diasteromers) is necessary in thecompound (I), the separation step in the first step of the above ProcessA is additionally carried out. If necessary, the reduction step in thesecond step of said Process A is also applied.

X₁, X₂ and Q in the above formulas (I)-(XIV) are as defined above and X₃is chlorine or bromine. The neutral solvent includes, for example,chloroform, ethyl acetate, dimethylformamide, etc. The polar neutralsolvent (A) includes, for example, alcohols, water, etc. The polarneutral solvent (B) includes, for example, tetrahydrofuran, dioxane,etc. The basic solvent includes, for example, pyridine, etc. The acidcatalyst includes, for example, sulfonic acids such as p-toluenesulfonicacid and the like; mineral acids such as hydrochloric acid and the like;Lewis acids such as zinc chloride and the like; etc. Thede-methanolating agent includes, for example, molecular sieves, etc. Thedehydrating agent includes, for example, anhydrous copper sulfate,sodium sulfate, molecular sieves, etc. The condensing agent includescarbodiimides such as dicyclohexylcarbodiimide and the like, etc. Thereducing catalyst includes palladium-carbon, etc. The organic acid andthe inorganic acid include, for example, formic acid, acetic acid,propionic acid, butyric acid, hydrochloric acid, sulfuric acid,phosphoric acid, etc.

Furthermore, specific synthesis examples of the intermediates (IV), (V)and (VI) are explained below, from which intermediates the compound ofthis invention is synthesized by Process A (direct process).

SYNTHESIS EXAMPLE 1 Synthesis of the Exo Form of3',4'-O-Benzylidene-Chartreusin (Intermidiate No. 501)

In 500 ml of anhydrous chloroform was dissolved 20 g of chartreusin,followed by adding thereto 23.8 g of benzaldehyde dimethylacetal, 2 g ofp-toluenesulfonic acid and 100 g of Molecular Sieves 5A 1/16, and theresulting mixture was subjected to reaction with stirring at roomtemperature for 1 hour.

After completion of the reaction, 6 ml of pyridine was added and theresulting mixture was filtered through Celite, after which the filtratewas concentrated to a volume of about 250 ml, and the resulting solutionwas purified by a silica gel column chromatography to obtain crystals ofa mixture of the exo form and the endo form of3',4'-O-benzylidene-chartreusin.

Subsequently, the aforesaid crystals were dissolved in 200 ml ofchloroform, followed by adding thereto 25 ml of a 0.01N hydrochloricacid-methanol solution prepared from concentrated hydrochloric acid andmethanol, and the resulting mixture was subjected to reaction withstirring at room temperature for 18 hours.

After completion of the reaction, several milliliters of pyridine wasadded, and the resulting mixture was filtered, after which the filtratewas concentrated under reduced pressure to obtain a mixture ofchartreusin and the exo form of 3',4'-O-benzylidene-chartreusin.Subsequently, this mixture was subjected to a silica gel columnchromatography to obtain crystals of the exo form of3',4'-O-benzylidene-chartreusin. Said crystals wee recrystallized from amixture of chloroform and ethanol to obtain 8.6 g of crystals of the exoform.

SYNTHESIS EXAMPLE 2 Synthesis of the Exo Form and the Endo Form of3',4'-O-Benzylidene-Chartreusins (Intermediate Nos. 501 and 502)

In 300 ml of anhydrous chloroform was dissolved 10.0 g of chartreusin,followed by adding thereto 30 ml of benzaldehyde, 1 g ofp-toluenesulfonic acid and 50 g of Molecular Sieves 4A 1/16, and theresulting mixture was subjected to reaction with stirring at roomtemperature for 20 hours. After completion of the reaction, the reactionmixture was filtered through Celite and the filtrate was concentrated toa volume of about 150 ml, after which the resulting solution wasseparated by several repetitions of a silica gel column chromatographyto obtain crystals of the exo form and the endo form of3',4'-O-benzylidene-chartreusin. The crystals of each isomer wererecrystallized from a mixture of chloroform and ethanol, whereby 2.7 gof crystals of the exo form and 4.8 g of crystals of the endo form wereobtained.

SYNTHESIS EXAMPLE 3 Synthesis of3',4'-O-(o-Fluorobenzylidene)-Chartreusin (A Mixture of the Exo Form andthe Endo Form at a Ratio of 1:6, Intermediate No. 503)

In 63 ml of anhydrous chloroform was dissolved 2.0 g of chartreusin,followed by adding thereto 3.3 ml of o-fluorobenzaldehyde, 200 mg ofp-toluenesulfonic acid and 6 g of Molecular Sieves 4A 1/16, and theresulting mixture was subjected to reaction with stirring at 40° to 50°C. for 24 hours. After completion of the reaction, the reaction mixturewas filtered through Celite, and the filtrate was concentrated, afterwhich the concentrate was purified by several repetitions of a silicagel column chromatography to obtain crystals. The crystals wererecrystallized from a mixture of chloroform and ethanol to obtain 630 mgof 3',4'-O-(o-fluorobenzylidene)-chartreusin (a mixture of the exo formand the endo form at a ratio of 1:6).

SYNTHESIS EXAMPLE 4 Synthesis of the Exo Form and the Endo Form of3',4'-O-(m-Fluorobenzylidene)-Chartreusin (Intermediate Nos. 504 and505)

In 250 ml of anhydrous chloroform was dissolved 5.0 g of chartreusin,followed by adding thereto 6.7 g of m-fluorobenzaldehyde dimethylacetal,1.4 g of p-toluenesulfonic acid and 25 g of Molecular Sieves 5A 1/16,and the resulting mixture was subjected to reaction with stirring at 40°to 45° C. for 5 hours. After completion of the reaction, 3.0 ml ofpyridine was added and the resulting mixture was filtered through Celiteafter which the filtrate was concentrated and the resulting crudecrystals were separated by several repetitions of a silica gel columnchromatography to obtain crystals of the exo form and the endo form of3',4'-O-(m-fluorobenzylidene)-chartreusin. The crystals of each isomerwas recrystallized from a mixture of chloroform and ethanol, whereby 503mg of crystals of the exo form and 480 mg of crystals of the endo formwere obtained.

SYNTHESIS EXAMPLE 5 Synthesis of the Endo Form of3',4'-O-(m-Trifluoromethylbenzylidene)-Chartreusin (Intermediate No.506)

In 30 ml of anhydrous chloroform was dissolved 1.0 g of chartreusin,followed by adding thereto 2.1 ml of m-trifluoromethylbenzaldehyde, 100mg of p-toluenesulfonic acid and 3 g of Molecular Sieves 4A 1/16, andthe resulting mixture was subjected to reaction with stirring at 20° to25° C. for 20 hours. After completion of the reaction, the reactionmixture was filtered through Celite and the filtrate was concentrated,after which the concentrate was subjected to several repetitions of asilica gel column chromatography to obtain crystals. The crystals wererecrystallized from a mixture of chloroform and ethanol to obtain 580 mgof the endo form of 3',4'-O-(m-trifluoromethylbenzylidene)-chartreusin.

SYNTHESIS EXAMPLE 6 Synthesis of 3',4'-O-(2-Furylmethylene)-Chartreusin(A Mixture of the Exo Form and the Endo Form at a Ratio of 1:1,Intermdiate No. 507)

In 50 ml of anhydrous chloroform was dissolved 1.8 g of chartreusin,followed by adding thereto 5.2 ml of furfural, 200 mg ofp-toluenesulfonic acid and 5 g of Molecular Sieves 4A 1/16, and thereaction was carried out with stirring at 20° to 25° C. for 24 hours.After completion of the reaction, the reaction mixture was filteredthrough Celite and the filtrate was concentrated, after which theconcentrate was purified by several repetitions of a silica gel columnchromatography to obtain crystals. The crystals were recrystallized froma mixture of chloroform, ethanol and ether to obtain 489 mg of3',4'-O-(2-furylmethylene)-chartreusin (a mixture of the exo form andthe endo form at a ratio of 1:1).

Intermediates Nos. 508 to 526 were synthesized according to SynthesisExamples 1 to 6 above. The structures and melting points ofintermediates Nos. 501 to 526 are tabulated in Table 1, and NMR data oftypical intermediates of them are shown in Table 2.

                  TABLE 1                                                         ______________________________________                                        Inter-                         Melting                                        medi- Structure [X.sub.1 = hydrogen] (Note 1)                                                                point                                          ate No.                                                                             X.sub.2          Isomer (Note 2)                                                                           (°C.)                               ______________________________________                                        501   Phenyl           Exo form    165.0-200.0                                502                    Endo form   262.0-266.5                                503   o-Fluorophenyl   Mixture (1:6)                                                                             258.0-269.0                                504   m-Fluorophenyl   Exo form    159.0-165.0                                505                    Endo form   252.0-265.0                                506   m-Trifluoromethylphenyl                                                                        Endo form   226.0-232.0                                507   2-Furyl          Mixture (1:1)                                                                             180.0-192.0                                508   p-Fluorophenyl   Exo form    155.0-167.0                                509                    Endo form   235.0-245.0                                510   o-Chlorophenyl   Endo form   225.0-234.5                                511   m-Chlorophenyl   Exo form    158.0-163.0                                512                    Endo form   243.0-255.0                                513   p-Chlorophenyl   Exo form    258.5-268.0                                514                    Endo form   213.5-222.0                                515   m-Bromophenyl    Endo form   255.0-263.0                                516   p-Bromophenyl    Exo form    275.0-282.0                                517                    Endo form   185.0-189.0                                518   2,4-Dichlorophenyl                                                                             Endo form   190.0-200.0                                519   o-Methylphenyl   Exo form    192.0-198.0                                520                    Endo form   238.0-243.0                                521   p-Methoxyphenyl  Exo form    283.0-295.0                                522   m-Nitrophenyl    Endo form   227.0-235.0                                523   2-Phenylethyl    Exo form    137.0-145.0                                524   3-Thienyl        Exo form    236.0-242.0                                525                    Endo form   260.0-272.0                                526   pentafluorophenyl            oily                                                                          substance                                  ______________________________________                                         (Note 1): X.sub.1 and X.sub.2 represent substituents in the intermediates     (IV), (V) or (VI).                                                            (Note 2): In the mixtures, the ratio is that of exo form to endo form.   

                                      TABLE 2                                     __________________________________________________________________________    Inter-                                                                        mediate                                                                            The Assignment of NMR (60 MHz, δ value, in CDCl.sub.3)             No.  A  B  C  D  E  F  G  H*       I  Others (or remarks)                     __________________________________________________________________________    501  1.30                                                                             1.48                                                                             2.83                                                                             3.40                                                                             5.27                                                                             5.89                                                                             6.32                                                                              7.17-8.23 (10H)                                                                       11.70                                                                            --                                      502  1.10                                                                             1.48                                                                             2.81                                                                             3.40                                                                             5.30                                                                             5.77                                                                             5.98                                                                              7.22-8.23 (10H)                                                                       11.67                                                                            --                                      504  1.33                                                                             1.49                                                                             2.84                                                                             3.43                                                                             5.31                                                                             5.91                                                                             6.33                                                                             7.00-8.30 (9H)                                                                         11.65                                                                            --                                      505  1.12                                                                             1.48                                                                             2.79                                                                             3.41                                                                             5.37                                                                             5.76                                                                             5.96                                                                             7.00-8.29 (9H)                                                                         11.62                                                                            --                                      506  1.11                                                                             1.46                                                                             2.74                                                                             3.36                                                                             5.28                                                                             5.67                                                                             5.93                                                                             7.08-8.18 (9H)                                                                         11.68                                                                            --                                      508  1.27                                                                             1.45                                                                             2.77                                                                             3.40                                                                             5.28                                                                             5.86                                                                             6.29                                                                             7.00-8.17 (9H)                                                                         11.57                                                                            --                                      509  1.09                                                                             1.46                                                                             2.79                                                                             3.41                                                                             5.31                                                                             5.74                                                                             5.94                                                                             7.00-8.21 (9H)                                                                         11.60                                                                            --                                      510  1.10                                                                             1.51                                                                             2.85                                                                             3.45                                                                             5.39                                                                             5.84                                                                             6.40                                                                             7.26-8.46 (9H)                                                                         11.63                                                                            --                                      512  1.15                                                                             1.47                                                                             2.79                                                                             3.40                                                                             5.31                                                                             5.70                                                                             5.90                                                                             7.14-8.27 (9H)                                                                         11.67                                                                            --                                      514  1.16                                                                             1.48                                                                             2.84                                                                             3.43                                                                             5.38                                                                             5.79                                                                             5.99                                                                             7.22-8.35 (9H)                                                                         11.57                                                                            --                                      515  1.17                                                                             1.49                                                                             2.80                                                                             3.47                                                                             5.41                                                                             5.82                                                                             5.98                                                                             7.20-8.38 (9H)                                                                         11.63                                                                            --                                      519  1.27                                                                             1.45                                                                             2.80                                                                             3.37                                                                             5.27                                                                             5.87                                                                             6.47                                                                             7.04-8.27 (9H)                                                                         11.67                                                                            2.48 (3H, s, Ar--CH.sub.3)              522  1.16                                                                             1.49                                                                             2.79                                                                             3.41                                                                             5.37                                                                             5.72                                                                             6.07                                                                             7.17-8.44 (9H)                                                                         11.60                                                                            --                                      524  1.34                                                                             1.48                                                                             2.83                                                                             3.42                                                                             5.30                                                                             5.89                                                                             6.42                                                                             7.00-8.34 (8H)                                                                         11.66                                                                            H* includes the                                                               thienyl group                           __________________________________________________________________________     A: (3H, d, J = 7Hz, --CH.sub.3),                                              B: (3H, d, J = 7Hz, --CH.sub.3),                                              C: (3H, s, Ar--CH.sub.3),                                                     D: (3H, s, --O--CH.sub.3),                                                    E: (1H, d, J = 8Hz, anomer proton),                                           F: (1H, d, J = 4Hz, anomer proton),                                           G: (1H, s, --O--CH--O--),                                                     H*: (aromatic proton),                                                        I: (1H, s, phenolic proton)                                              

SYNTHESIS EXAMPLE 7 Synthesis of 3',4'-O-Isopropylidene-Chartreusin(Intermediate No. 527)

In 330 ml of anhydrous chloroform was dissolved 14.0 g of chartreusin,followed by adding thereto 100 ml of 2,2-dimethoxypropane and 300 mg ofp-toluenesulfonic acid, and the resulting mixture was subjected toreaction with stirring at 25° to 30° C. for 8 hours. After completion ofthe reaction, the reaction mixture was filtered and an aqueous sodiumhydrogencarbonate solution was added, after which the resulting mixturewas extracted with chloroform. The chloroform layer was washed with anaqueous sodium chloride solution and dried over anhydrous sodiumsolfate. Then the chloroform was removed by distillation under reducedpressure to obtain an oily substance. Subsequently, the oily substancewas crystallized from a mixed solvent of chloroform, ethanol and hexaneto obtain 12.5 g of 3',4'-O-isopropylidene-chartreusin.

NMR (60 MHz, δ values in CDCl₃): 1.20-1.73 (12H, CH₃ x4), 2.87 (3H, s,Ar--CH₃), 3.43 (3H, s, O--CH₃), 5.23 (1H, m, anomer proton), 5.90 (1H,m, anomer proton), 7.23-8.40 (5H, aromatic proton), 11.57 (1H, phenolicproton)

SYNTHESIS EXAMPLE 8 Synthesis of 3',4'-O-Isobutylidene-Chartreusin(Intermediate No. 528)

In 20 ml of anhydrous chloroform was dissolved 500 mg of chartreusin,followed by adding thereto 30 ml of anhydrous methyl ethyl ketone, 800mg of anhydrous copper sulfate and 50 mg of p-toluenesulfonic acid, andthe resulting mixture was subjected to reaction with stirring at 25° to30° C. for 48 hours. After completion of the reaction, the reactionmixture was filtered and an aqueous sodium hydrogencarbonate was addedto the filtrate, after which the resulting mixture was extracted withchloroform. The chloroform layer was washed with an aqueous sodiumchloride solution and dried. Then the chloroform was removed bydistillation under reduced pressure to obtain an oily substance.Subsequently, the oily substance was purified by a silica gel columnchromatography and then crystallized from a mixed solvent of chloroform,ethanol and hexane to obtain 125 mg of3',4'-O-isobutylidene-chartreusin.

NMR (60 MHz, δ values in CDCl₃ --CD₃ SOCD₃): 1.00-1.73 (14H, 3Hx4, CH₂x1), 2.85 (3H, s, Ar--CH₃), 5.73 (1H, m, anomer proton), 7.27-8.27 (5H,aromatic proton), 11.67 (1H, phenodic proton)

Intermediate Nos. 529 to 531 were synthesized according to SynthesisExamples 7 and 8 above.

The structures and melting points of the intermediate Nos. 527 and 531are tabulated in Table 3.

                  TABLE 3                                                         ______________________________________                                        Intermediate                                                                           Structure (Note 1)   Melting point                                   No.      X.sub.1     X.sub.2      (°C.)                                ______________________________________                                        527      Methyl      Methyl       168.0-170.0                                 528      Methyl      Ethyl        203.0-208.0                                 529      Hydrogen    Ethyl        197.0-206.0                                 530      Hydrogen    Acetylmethyl 192.5-202.0                                 531      Pentamethylene (cyclohexylidene)                                                                   243.5-253.5                                     ______________________________________                                         (Note 1): X.sub.1 and X.sub.2 represent substituents in the intermediate      (IV).                                                                    

Next, specific synthesis examples of the intermediates (X) and (XIII)are described below, via which intermediate the compound of thisinvention is synthesized by Process B (via monosilyl form) and Process C(via disilyl form). Typical examples of the intermediate (XII) arelisted in Table 4.

SYNTHESIS EXAMPLE 9

In 18.4 ml of anhydrous dimethylformamide was dissolved 500 mg of the3',4'-O-isopropylidene-chartreusin (intermediate No. 527) obtained inSynthesis Example 7 above, after which 400 mg of imidazole and 444 mg oftert-butyldimethylchlorosilane were added, and the resulting mixture wassubjected to reaction with stirring at 0° C. for 6 hours. Aftercompletion of the reaction, the reaction mixture was poured into anaqueous sodium hydrogencarbonate solution and the resulting mixture wasextracted with chloroform. The chloroform layer was dried and thesolvent was removed by distillation under reduced pressure to obtain anoily substance. The oily substance was dissoved in 10 ml ofhexamethyltriamide phosphate, followed by adding thereto 85 mg ofpotassium fluoride and 147 mg of potassium hydrogencarbonate, and theresulting mixture was subjected to reaction with stirring at 25° C. for30 minutes. After completion of the reaction, the reaction mixture waspoured into an aqueous sodium hydrogencarbonate solution and theresulting mixture was extracted with chloroform. The chloroform layerwas dried and the solvent was removed by distillation under reducedpressure to obtain an oily substance. Subsequently, the oily substancethus obtained was subjected to a silica gel column chromatography toobtain crystals, which were then recrystallized from a mixed solvent ofethanol, chloroform and hexane to obtain 520 mg of3',4'-O-isopropylidene-2"-O-(tert-butyldimethylsilyl)-chartreusin havinga melting point of 130°-135° C.

NMR (60 MHz, δ values in CDCl₃): -0.43 (3H, s, Si--CH₃), -0.22 (3H, s,Si--CH₃), 0.47 (9H, s, Si-tert-C₄ H₉), 1.17-1.77 (12H, CH₃ x4), 2.90(3H, s, Ar--CH₃), 3.40 (3H, s, O--CH₃), 5.50 (2H, m, anomer proton x 2),7.23-8.40 (5H, aromatic proton), 11.66 (1H, phenolic proton)

SYNTHESIS EXAMPLE 10 Synthesis of3',4'-O-Isopropylidene-2",4"-Di(Tert-Butyldimethylsilyl)-Chartreusin(Intermediate No. 533)

In 18.4 ml of anhydrous dimethylformamide was dissolved 500 mg of the3',4'-O-isopropylidene-chartreusin obtained in Synthesis Example 7above, after which 800 mg of imidazole and 888 mg oftert-butyldimethylchlorosilane were added, and the resulting mixture wassubjected to reaction with stirring at 55° to 60° C. for 48 hours. Aftercompletion of the reaction, the reaction mixture was poured into anaqueous sodium hydrogencarbonate solution and the resulting mixture wasextracted with chloroform. The chloroform layer was dried and thesolvent was removed by distillation under reduced pressure to obtain anoily substance. The oily substance was dissolved in 15 ml ofhexamethyltriamide phosphate, followed by adding thereto 85 mg ofpotassium fluoride and 147 mg of potassium hydrogencarbonate, and theresulting mixture was subjected to reaction with stirring at 25° C. for1 hour. After completion of the reaction, the reaction mixture waspoured into an aqueous sodium hydrogencarbonate solution and theresulting mixture was extracted with chloroform. The chloroform layerwas dried and the solvent was removed by distillation under reducedpressure to obtain an oily substance. Subsequently, the oily substancethus obtained was subjected to a silica gel column chromatography toobtain 608 mg of3',4'-O-isopropylidene-2",4"-O-di(tert-butyldimethylsilyl)-chartreusinhaving a melting point of 119.5°-125.0° C.

NMR (60 MHz, δ values in CDCl₃): -0.38 (3H, s, 2-O-Si--CH₃), -0.18 (3H,s, 2"-O-Si--CH₃), 0.05 (6H, s, 4"-O-Si--CH₃ x2), 0.48 (9H, s,2"-O-Si-tert-C₄ H₉), 0.88 (9H, s, 4"-O-Si-tert--C₄ H₉) 1.10-1.80 (12H,CH₃ x4), 2.28 (3H, s, Ar-CH₃), 3.33 (3H, s, O-CH₃), 5.43 (2H, m, anomerproton x 2), 7.30-8.30 (5H, aromatic proton), 11.63 (1H, phenolicproton)

                                      TABLE 4                                     __________________________________________________________________________    Inter-                                                                        mediate                                                                            (Note 1)                (Note 2)                                                                            Melting point                              No.  Q                       Rf value                                                                            (°C.)                               __________________________________________________________________________    534                                                                                 ##STR19##              0.32  --                                         535  (CH.sub.2).sub.2 NHCHO  0.16  --                                         536  (CH.sub.2).sub.2 NHCOCH.sub.3                                                                         0.20  212.0-219.0                                537  (CH.sub.2).sub.2 NHCOCCl.sub.3                                                                        0.28  193.5-199.0                                538  (CH.sub.2).sub.2 NHCOOCH.sub.2(phenyl)                                                                0.32  --                                         539  (CH.sub.2).sub.3 NHCOOCH.sub.2(phenyl)                                                                0.33  229.0-234.5                                540  (CH.sub.2).sub.4 NHCOCF.sub.3                                                                         0.25  --                                         541  (CH.sub.2).sub.5 NHCOOCH.sub.2(phenyl)                                                                0.33  243.5-249.0                                542  (CH.sub.2).sub.11 NHCOCH.sub.3                                                                        0.23  218.5-227.5                                543                                                                                 ##STR20##              0.26  222.0-230.5                                544                                                                                 ##STR21##              0.28  157.0-176.0                                545                                                                                 ##STR22##              0.32  --                                         546                                                                                 ##STR23##              0.26  --                                         547  (CH.sub.2).sub.2 NHCOCH.sub.2 NHCOOCH.sub.2(phenyl)                                                   0.25  --                                         548  CH.sub.3                0.28  231.0-252.5                                549  CH.sub.2 CH(CH.sub.3).sub.2                                                                           0.33  --                                         550  (CH.sub.2).sub.4 CH.sub.3                                                                             0.27  245.0-250.5                                551                                                                                 ##STR24##              0.28  190.5-194.5                                552                                                                                 ##STR25##              0.35  216.5-225.0                                553                                                                                 ##STR26##              0.31  --                                         554  (CH.sub.2).sub.2(cyclohexyl)                                                                          0.32  224.0-227.5                                555  CHCHCHCHCH.sub.3        0.33  188.0-204.0                                556                                                                                 ##STR27##              0.30  --                                         557  (CH.sub.2).sub.2 CCH    0.28  245.5-256.0                                558                                                                                 ##STR28##              0.30  --                                         559                                                                                 ##STR29##              0.29  --                                         560  CH.sub.2 O(phenyl)      0.32  208.5-227.0                                561  (CH.sub.2).sub.3 OCH.sub.2(phenyl)                                                                    0.32  --                                         562  CH.sub.2 S(phenyl)      0.31  --                                         563  CH.sub.2 OCOCH.sub.3    0.32  --                                         564  (CH.sub.2).sub.2 COCH.sub.3                                                                           0.29  261.0-268.5                                565  (CH.sub.2).sub.2 COOCH.sub.3                                                                          0.29  --                                         566  (o-chlorophenyl)        0.28  245.0-249.5                                567  (p-cyanophenyl)         0.32  231.5-235.0                                568  (p-trifluoromethylphenyl)                                                                             0.30  255.0-272.5                                __________________________________________________________________________     Note 1: Q is a substituent in the intermediate (XII).                         Note 2: Rf values were measured by a silica gel thinlayer chromatography      (Merk Silica Gel 60GF.sub.254) using a mixed solvent of chloroform and        methanol (8:1) as a developing solvent.                                  

Next, specific synthesis examples of the compounds of this invention aredescribed. The melting points of the compounds of this inventiondescribed in the synthesis examples and the NMR data of typicalcompounds of this invention are hereinafter collectively described.

SYNTHESIS EXAMPLE 11 Synthesis of the Exo Form of6-O-(N,N-Diethyl-β-Alanyl)-3',4'-O-Benzylidene-Chartreusin Hydrochloride(Referred to Hereinafter as Compound No. 8)

In a mixture of 1.4 ml of anhydrous pyridine and 0.7 ml of anhydrouschloroform was dissolved 100 mg of the exo form of3',4'-O-benzylidene-characteusin (intermediate No. 501) obtained inSynthesis Example 1 above, after which 60 mg of N',N-diethyl-β-alanineand 113 mg of dicyclohexylcarbodiimide were added, and the resultingmixture was subjected to reaction at room temperature for 4 hours.

After completion of the reaction, 10 ml of a mixed solvent of a smallamount of methanol and 10 ml of a mixed solvent of chloroform and ethylacetate (˜1:10) was added. Then, the resulting mixture was filtered andthe filterate was concentrated under reduced pressure, after which theoily substance thus obtained was separated by a short silica gel columnchromatography, to obtain about 100 mg of a product.

The aforesaid product was dissolved in 20 ml of a mixed solvent ofchloroform and ethyl acetate (˜1:10) and the resulting solution wasextracted with diluted hydrochloric acid. After the hydrochloric acidlayer was washed with ethyl acetate, sodium chloride was added and theresulting mixture was extracted with chloroform. The chloroform layerwas washed with an aqueous sodium chloride solution, thereafter driedover anhydrous sodium sulfate and then concentrated under reducedpressure to obtain 33 mg of the exo form of6-O-(N,N-diethyl-β-alanyl)-3',4'-O-benzylidene-chartreusin.

In a mixture of 0.39 ml of a 0.1N aqueous hydrochloric acid solution and10 ml of water was dissolved 33 mg of this chartreusin derivative, andthe resulting solution was washed with ethyl acetate and thenfreeze-dried to obtain 33 mg of the desired compound.

SYNTHESIS EXAMPLE 12 Synthesis of the Exo Form of6-O-(N,N-Dimethyl-β-Amino-Isobutyryl)-3',4'-O-Benzylidene-ChartreusinHydrochloride (Hereinafter Referred to as Compound No. 1)

In a mixture of 1.7 ml of anhydrous pyridine and 0.8 ml of anhydrouschloroform was dissolved 120 mg of the exo form of3',4'-O-benzylidene-chartreusin (intermediate No. 501) obtained inSynthesis Example 1 above, after which 43 mg ofN,N-dimethyl-β-aminoisobutyric acid and 102 mg ofdicyclohexylcarbodiimide were added, and the resulting mixture wassubjected to reaction with stirring at room temperature for 24 hours.

After completion of the reaction, 79 mg of the desired compound wasobtained in the same manner as in Synthesis Example 11 above.

SYNTHESIS EXAMPLE 13 Synthesis of the Exo Form of6-O-(N-Trifluoroacetyl-β-Amino-Isobutyryl)-3',4'-O-Benzylidene-Chartreusin(Hereinafter Referred to as Compound No. 12)

In a mixture of 1.4 ml of anhydrous pyridine and 0.7 ml of anhydrouschloroform was dissolved 100 mg of the exo form of3',4'-O-benzylidene-chartreusin (intermediate No. 501) obtained inSynthesis Example 1 above, after which 55 mg ofN-trifluoroacetyl-β-aminoisobutyric acid and 85 mg ofdicyclohexylcarbodiimide were added, and the resulting mixture wassubjected to reaction with stirring at room temperature for 1 hour.

After completion of the reaction, a small amount of methanol was added.Then, the resulting mixture was filtered and the filtrate wasconcentrated under reduced pressure, after which the oily substance thusobtained was subjected to a silica gel thin-layer chromatography toobtain crystals. Subsequently, said crystals were recrystallized from amixture of chloroform and ethanol to obtain 85 m of the desiredcompound.

SYNTHESIS EXAMPLE 14 Synthesis of the Exo Form of6-O-(N-Trifluoroacetyl-2-Amino-Cyclohexanecarbonyl)-3',4'-O-Benzylidene-Chartreusin(Hereinafter Referred to as Compound Nos. 118 and 26)

In a mixture of 0.8 ml of anhydrous pyridine and 0.4 ml of anhydrouschloroform was dissolved 60 mg of the exo form of3',4'-O-benzylidene-chartreusin (intermediate No. 501) obtained inSynthesis Example 1 above, after which 49 mg ofN-trifluoroacetyl-2-amino-cyclohexanecarboxylic acid and 59 mg ofdicyclohexylcarbodiimide were added, and the resulting mixture wassubjected to reaction with stirring at room temperature for 2 hours.

After completion of the reaction, a small amount of methanol was added.Then, the resulting mixture was filtered and the filtrate wasconcentrated under reduced pressure, after which the oily substance thusobtained was separated by a silica gel thin-layer chromatography toobtain crystals of the two isomers. The crystals of each isomer wererecrystallized from a mixture of chloroform, ethanol and ether to obtain21 mg of one of the isomers (referred to hereinafter as compound No.118) and 21 mg of the other (referred to hereinafter as compound No.26).

Compound No. 118 [Rf value: 0.650 (a silica gel thin-layerchromatography (Merk Silica Gel 60GF₂₅₄, developingsolvent:chloroform:methanol=15:1))]

Compound No. 26 [Rf value: 0.570 (a silica gel thin-layer chromatography(Merk Silica Gel 60GF₂₅₄, developing solvent:chloroform:methanol=15:1))]

SYNTHESIS EXAMPLE 15 Synthesis of the Exo Form of6-O-(N-Trifluoroacetyl-2-Amino-Cyclohexanecarbonyl)-3',4'-O-(m-Fluorobenzylidene)-Chartreusin(Referred to Hereinafter as Compound Nos. 117 and 27)

In a mixture of 0.7 ml of anhydrous pyridine and 0.3 ml of anhydrouschloroform was dissolved 50 mg of the exo form of3',4'-O-(m-fluorobenzylidene)-cartreusin (intermediate No. 504) obtainedin Synthesis Example 4 above, after which 40 mg ofN-trifluoroacetyl-2-aminocyclohexanecarboxylic acid and 48 mg ofdicyclohexylcarbodiimide were added, and the resulting mixture wassubjected to reaction with stirring at room temperature for 2 hours.After completion of the reaction, 11 mg of one of the isomers (referredto hereinafter as compound No. 117) and 12 mg of the other (referred tohereinafter as compound No. 27), were obtained.

Compound No. 117 [Rf value: 0.645 (a silica gel thin-layerchromatography (Merk Silica Gel 60GF₂₅₄, developing solvent:chloroformmethanol=15:1))]

Compound No. 27 [Rf value: 0.560 (a silica gel thin-layerchloromatography (Merk Silica Gel 60GF₂₅₄, developingsolvent:chloroform:methanol=15:1))]

SYNTHESIS EXAMPLE 16 Synthesis of the Endo Form of6-O-(N-Trifluoroacetyl-β-Alanyl)-3',4'-O-Benzylidene-Chartreusin(Referred to Hereinafter as Compound No. 28)

In a mixture of 1.5 ml of anhydrous pyridine, 1.5 ml of anhydrous ethylacetate and 1.5 ml of anhydrous chloroform was dissolved 110 mg of theendo form of 3',4'-O-benzylidene-chartreusin (intermediate No. 502)obtained in Synthesis Example 2 above, after which 70 mg ofN-trifluoroacetyl-β-alanine and 109 mg of dicyclohexylcarbodiimide wereadded, and the resulting mixture was subjected to reaction with stirringat room temperature for 2 hours. After completion of the reaction,crystals were obtained in the same manner as in Synthesis Example 13above. Subsequently, said crystals were recrystallized from a mixture ofchloroform, ethanol and ether to obtain 100 mg of the desired compound.

SYNTHESIS EXAMPLE 17 Synthesis of6-O-(N-Trifluoroacetyl-β-Alanyl)-3',4'-O-Isopropylidene-Chartreusin(Referred to Hereinafter as Compound No. 49)

In a mixture of 1.1 ml of anhydrous pyridine and 4.4 ml of anhydrousethyl acetate was dissolved 150 mg of the3',4'-O-isopropylidene-chartreusin (intermediate No. 527) obtained inSynthesis Example 7 above, after which 164 mg ofN-trifluoroacetyl-β-alanine and 137 mg of dicyclohexylcarbodiimide wereadded, and the resulting mixture was subjected to reaction with stirringat 35° C. for 2 hours. After completion of the reaction, 0.5 ml ofmethanol was added, and the resulting mixture was filtered, after whichthe filtrate was concentrated under reduced pressure, and the oilysubstance thus obtained was separated by a silica gel thin-layerchromatography to obtain a viscous oily substance. Subsequently, saidviscous oily substance was dissolved in a small amount of a mixedsolvent of chloroform and ethanol, and ether was poured thereinto toform a precipitate, which was then filtered to obtain 40 mg of thedesired compound.

SYNTHESIS EXAMPLE 18 Synthesis of the Exo Form of6-O-(N-Carbobenzyloxy-S-Oxomethionyl)-3',4'-O-Benzylidene-Chartreusin(Hereinafter Referred to as Compound No. 79)

In a mixture of 0.7 ml of anhydrous pyridine and 0.3 ml of anhydrouschloroform was dissolved 50 mg of the exo form of3',4'-O-benzylidene-chartreusin (intermediate No. 501) obtained inSynthesis Example 1 above, after which 56 mg ofN-Carbobenzyloxymethionine and 57 mg of dicyclohexylcarbodiimide wereadded, and the resulting mixture was subjected to reaction with stirringat room temperature for 1 hour.

After completion of the reaction, a small amount of methanol was added.Then, the resulting mixture was filtered and the filtrate wasconcentrated under reduced pressure, after which the oily substance thusobtained was dissolved in about 20 ml of chloroform and oxidized withvigorous stirring in the atmosphere. After completion of the reaction,the reaction mixture was concentrated under reduced pressure, and theconcentrate was subjected to a silica gel thin-layer chromatography toobtain crystals. Subsequently, said crystals were recrystallized from amixture of chloroform, ethanol and ether to obtain 16 mg of the desiredcompound.

SYNTHESIS EXAMPLE 19 Synthesis of6-O-(N-Carbobenzyloxy-6-Amino-n-Hexanoyl)-3',4'-O-Isopropylidene-Chartreusin(Referred to Hereinafter as Compound No. 111)

In a mixture of 1.5 ml of anhydrous pyridine and 5.9 ml of anhydrousethyl acetate was dissolved 200 mg of the3',4'-O-Isopropylidene-Chartreusin (intermediate No. 527) obtained inSynthesis Example 7 above, after which 462 mg ofN-Carbobenzyloxy-6-Amino-n-hexanoic acid and 358 mg ofdicyclohexylcarbodiimide were added, and the resulting mixture wassubjected to reaction with stirring at 30° C. for 50 hours. Aftercompletion of the reaction, 145 mg of the desired compound was obtainedin the same manner as in Synthesis Example 17 above.

SYNTHESIS EXAMPLE 20 Synthesis of the Exo Form of6-O-(N-Carbobenzyloxy-Glycyl-Glycyl-Glycyl)-3',4'-O-Benzylidene-Chartreusin(Hereinafter Referred to as Compound No. 114)

In a mixture of 2.8 ml of anhydrous pyridine and 0.7 ml of anhydrouschloroform was added 100 mg of the exo form of3',4'-O-Benzylidene-Chartreusin (intermediate No. 501) obtained inSynthesis Example 1 above, after which 104 mg ofN-Carbobenzyloxy-Glycyl-Glycyl-glycine and 85 mg ofdicyclohexylcarbodiimide were added, and the resulting mixture wassubjected to reaction with stirring at room temperature for 72 hours.

After completion of the reaction, a small amount of methanol was added.Then the resulting mixture was concentrated under reduced pressure, andthe solid thus obtained was washed with chloroform and then with ethylacetate. The solid thus washed was dissolved in a mixed solvent ofethanol and chloroform, and the resulting solution was filtered, afterwhich the filtrate was concentrated under reduced pressure, and theconcentrate was subjected to a silica gel thin-layer chromatography toobtain crystals. Subsequently, said crystals were recrystallized from amixed solvent of pyridine, chloroform and ether to obtain 24 mg of thedesired compound.

SYNTHESIS EXAMPLE 21 Synthesis of the Endo Form of6-O-(m-Dimethylaminobenzoyl)-3',4'-O-(m-Fluorobenzylidene)-Chartreusin(Referred to Hereinafter as Compound No. 158)

In a mixture of 0.9 ml of anhydrous pyridine and 0.5 ml of anhydrouschloroform was dissolved 70 mg of the endo form of3',4'-O-(m-Fluorobenzylidene)-Chartreusin (intermediate No. 505)obtained in Synthesis Example 4 above, after which 31 mg ofm-dimethylaminobenzoic acid and 58 mg of dicyclohexycarbodiimide wereadded, and the resulting mixture was subjected to reaction with stirringat room temperature for 20 hours.

After completion of the reaction, a small amount of methanol was added.Then, the resulting mixture was filtered and the filtrate wasconcentrated under reduced pressure, after which the oily substance thusobtained was subjected to a silica gel thin-layer chromatography toobtain crystals. Subsequently, said crystals were recrystallized from amixture of chloroform, ethanol and ether to obtain 73 mg of the desiredcompound.

SYNTHESIS EXAMPLE 22 Synthesis of the Endo Form of6-O-(Trans-2-Methyl-2-Butenoyl)-3',4'-O-(m-Trifluoromethylbenzylidene)Chartreusin(Referred to Hereinafter as Compound No. 161)

In a mixture of 4.0 ml of anhydrous pyridine, 3.0 ml of anhydrous ethylacetate and 5.0 ml of anhydrous chloroform was dissolved 200 mg of theendo form of 3',4'-O-(m-Trifluoromethylbenzylidene)-Chartreusin(intermediate No. 506) obtained in Synthesis Example 5 above, afterwhich 200 mg of tiglic acid and 400 mg of dicyclohexylcarbodiimide wereadded, and the reaction was carried out with stirring at roomtemperature for 80 hours.

After completion of the reaction, a small amount of methanol was added.Then, the resulting mixture was filtered and the filtrate wasconcentrated under reduced pressure, after which the oily substance thusobtained was subjected to a silica gel column chromatography to obtaincrystals. Subsequently, said crystals were recrystallized from a mixtureof chloroform, ethanol and ether to obtain 64 mg of the desiredcompound.

SYNTHESIS EXAMPLE 23 Synthesis of the Exo Form of6-O-(3-Methyl-n-Butyryl)-3',4'-O-Benzylidene-Chartreusin (Referred toHereinafter as Compound No. 169)

In a mixture of 1.0 ml of anhydrous pyridine, 2.0 ml of anhydrous ethylacetate and 1.0 ml of anhydrous chloroform was dissolved 40 mg of theexo form of 3',4'-O-Benzylidene-Chartreusin (intermediate No. 501)obtained in Synthesis Example 1 above, after which 0.03 ml of3-methyl-n-butyric acid and 60 mg of dicyclohexylcarbodiimide wereadded, and the reaction was carried out with stirring at roomtemperature for 21 hours.

After completion of the reaction, 28 mg of the desired compound wasobtained in the same manner as in Synthesis Example 22 above.

SYNTHESIS EXAMPLE 24 Synthesis of the Exo Form of6-O-(n-Butyryl)-3',4'-O-Benzylidene-Chartreusin (Referred to Hereinafteras Compound No. 191)

In a mixture of 0.7 ml of anhydrous pyridine, 0.7 ml of anhydrous ethylacetate and 0.7 ml of anhydrous chloroform was dissolved 50 mg of theexo form of 3',4'-O-Benzylidene-Chartreusin (intermediate No. 501)obtained in Synthesis Example 1 above, after which 0.02 ml of n-butyricacid and 57 mg of dicyclohexylcarbodiimide were added, and the reactionwas carried out with stirring at room temperature for 6 hours.

After completion of the reaction, 41 mg of the desired compound wasobtained in the same manner as in Synthesis Example 22 above.

SYNTHESIS EXAMPLE 25 Synthesis of the Exo Form of6-O-(N-Isopropyl-β-Amino-Isobutyryl)-3',4'-O-Benzylidene-ChartreusinHydrochloride (Referred to Hereinafter as Compound No. 2)

In a mixture of 1.2 ml of tetrahydrofuran and 0.45 ml of a 0.1N aqueoushydrochloric acid solution was dissolved 40 mg of the exo form of6-O-(N-Carbobenzyloxy-N-Isopropyl-β-Amino-isobutyryl)-3',4'-O-benzylidenechartreusin(Referred to Hereinafter as Compound No. 135) obtained by a processaccording to Synthesis Examples 13 to 24 above, after which 20 mg of 5%palladium-carbon was added, and the resulting mixture was stirred in ahydrogen stream at 0° C. for 1.5 hours. After the stirring, 10 ml ofwater was added and the resulting mixture was filtered through Celite.The filtrate was washed several times with ethyl acetate and thenfreeze-dried to obtain 34 mg of the desired compound.

SYNTHESIS EXAMPLE 26 Synthesis of the Exo Form of6-O-(β-Amino-Isobutyryl)-3',4'-O-Benzylidene-Chartreusin Phosphate(Referred to Hereinafter as Compound No. 6)

In a mixture of 1.9 ml of tetrahydrofuran and 1.9 ml of a 0.1N aqueousphosphoric acid solution was dissolved 60 mg of the exo form of6-O-(N-Carbobenzyloxy-β-Amino-Isobutyryl)-3,4-O-Benzylidene-Chartreusin(Referred to Hereinafter as Compound No. 69) obtained by a processaccording to Synthesis Examples 13 to 24 above, after which 15 mg of 5%palladium-carbon was added, and the resulting mixture was stirred in ahydrogen stream at room temperature for 1 hour. After the stirring, 20ml of water was added and the resulting mixture was filtered throughCelite. The filtrate was washed several times with ethyl acetate andthen freeze-dried to obtain 46 mg of the desired compound.

SYNTHESIS EXAMPLE 27 Synthesis of the Exo Form of6-O-(4-Hydroxy-n-Butyryl)-3',4'-O-Benzylidene-Chartreusin (Referred toHereinafter as Compound No. 147)

In a mixture of 5.0 ml of tetrahydrofuran and 3.0 ml of methanol wasdissolved 35 mg of the exo form of 06-O-(4-benzyloxy-n-butyryl)-3',4'-O-Benzylidene-Chartreusin (Referred toHereinafter as Compound No. 165) obtained by a process according toSynthesis Examples 13 to 24 above, after which 55 mg of 5%palladium-carbon was added, and the resulting mixture was stirred in ahydrogen stream at room temperature for 24 hours.

After the stirring, the mixture was filtered, after which the filtratewas concentrated under reduced pressure and purified by a silica gelthin-layer chromatography to obtain crystals. Subsequently, the crystalswere recrystallized from a mixture of chloroform, ethanol and ether toobtain 4 mg of the desired compound.

SYNTHESIS EXAMPLE 28 Synthesis of6-O-(N-Acetyl-β-Alanyl)-3',4'-O-Isopropylidene-Chartreusin (Referred toHereinafter as Compound No. 87)

(1) In a mixture of 3 ml of anhydrous pyridine and 12 ml of anhydrousethyl acetate was dissolved 474 mg of the3',4'-O-Isopropylidene-2"-O-tert-butyldimethylsilylchartreusin(intermediate No. 532) obtained in Synthesis Example 9 above, afterwhich 368 mg of N-acetyl-8-alanine and 620 mg ofdicyclohexylcarbodiimide were added, and the reaction was carried outwith stirring at 25° C. for 20 hours.

After completion of the reaction, the reaction mixture was filtered andthe filtrate was concentrated under reduced pressure to obtain an oilysubstance.

The oily substance was purified by a silica gel column chromatographyand then dissolved in a mixture of 12 ml of tetrahydrofuran and 6 ml of3N hydrochloric acid, and the resulting solution was subjected toreaction at 25° C. for 15 hours.

After completion of the reaction, the reaction mixture was neutralizedwith an aqueous sodium hydrogencarbonate solution and extracted withchloroform, after which the chloroform layer was dried and the solventwas removed by distillation under reduced pressure to obtain yellowpowder of 6-O-(N-acetyl-β-Alanyl)-Chartreusin (intermediate No. 536).

(2) The aforesaid powder was washed with ether and dissolved in 30 ml ofanhydrous chloroform, followed by adding thereto 3.7 ml of2,2'-dimethoxypropane and 10 mg of p-toluenesulfonic acid, and theresulting mixture was subjected to reaction with stirring at 25° C. for15 hours.

After completion of the reaction, an aqueous sodium hydrogencarbonatesolution was added, and the resulting mixture was extracted withchloroform, after which the chloroform layer was dried and the solventwas removed by distillation under reduced pressure to obtain a crudeproduct.

The crude product was purified by a silica gel thin-layer chromatographyto obtain crystals. Subsequently, the crystals were recrystallized froma mixture of chloroform, ethanol and hexane to obtain 355 mg of thedesired compound.

SYNTHESIS EXAMPLE 29 Synthesis of6-O-(3-Cryclohexyl-Propionyl)-3',4'-O-Isopropylidene-Chartreusin(Referred to Hereinafter as Compound No. 240)

(1) In a mixture of 5 ml of anhydrous pyridine, 5 ml of anhydrouschloroform and 5 ml of anhydrous ethyl acetate was dissolved 400 mg ofthe 3',4'-O-Isopropylidene-2'-O-tert-butyldimethylsilyl-Chartreusin(intermediate No. 532) obtained in Synthesis Example 9 above, afterwhich 0.32 ml of 3-cyclohexylpropionic acid and 620 mg ofdicyclohexylcarbodiimide were added, and the reaction was carried outwith stirring at 25° C. for 20 hours.

After completion of the reaction, a small amount of methanol was added,after which the resulting mixture was filtered, and the filtrate wasconcentrated under reduced pressure to obtain an oily substance.

The oily substance was purified by a silica gel column chromatographyand then dissolved in a mixture of 10 ml of tetrahydrofuran and 5 ml of3N hydrochloric acid, and the resulting solution was subjected toreaction at 25° C. for 5 hours.

After completion of the reaction, the reaction mixture was neutralizedwith an aqueous sodium hydrogencarbonate solution and extracted withchloroform, after which the chloroform layer was dried and the solventwas removed by distillation under reduced pressure to obtain yellowpowder of 6-O-(3-cyclohexyl-Propionyl)-Chartreusin (intermediate No.554).

(2) The aforesaid powder was washed with ether and dissolved in 25 ml ofanhydrous chloroform, followed by adding thereto 3.0 ml of2,2-dimethoxypropane and 10 mg of p-toluenesulfonic acid, and theresulting mixture was subjected to reaction with stirring at 25° C. for15 hours.

After completion of the reaction, an aqueous sodium hydrogencarbonatesolution was added, and the resulting mixture was extracted withchloroform, after which the chloroform layer was dried and the solventwas removed by distillation under reduced pressure to obtain a crudeproduct.

The crude product was purified by a silica gel thin-layer chromatographyto obtain crystals. Subsequently, the crystals were recrystallized froma mixture of chloroform, ethanol and ether to obtain 265 mg of thedesired compound.

SYNTHESIS EXAMPLE 30 Synthesis of6-O-(N-Trichloroacetyl-β-Alanyl)-3',4'-O-Isopropylidene-Chartreusin(Referred to Hereinafter as Compound No. 112)

(1) In a mixture of 0.9 ml of anhydrous pyridine and 3.7 ml of anhydrousethyl acetate was dissolved 170 mg of the3',4'-O-Isopropylidene-2",4"-O-di(tert-butyldimethylsilyl)-Chartreusin(intermediate No. 533) obtained in Synthesis Example 10 above, afterwhich 220 mg of N-trichloroacetyl-β-alanine and 193 mg ofdicyclohexylcarbodiimide were added, and the resulting mixture wassubjected to reaction with stirring at 25° C. for 19 hours. Aftercompletion of the reaction, the reaction mixture was filtered and thefiltrate was concentrated under reduced pressure to obtain an oilysubstance.

The oily substance was purified by a silica gel column chromatographyand then dissolved in a mixture of 3.7 ml of tetrahydrofuran and 1.9 mlof 3N hydrochloric acid, and the resulting solution was subjected toreaction with stirring at 25° C. for 15 hours. After completion of thereaction, the reaction mixture was neutralized with an aqueous sodiumhydrogencarbonate solution and extracted with chloroform, after whichthe chloroform layer was dried and the solvent was removed bydistillation under reduced pressure to obtain 128 mg of yellow powder of6-O-(N-trichloroacetyl-β-alanyl)-chartreusin (intermediate No. 537).

(2) According to Synthesis Example 28 (2) above, 128 mg of the powderwas subjected to acetonation to obtain 100 mg of the desired compound.

SYNTHEIS EXAMPLE 31 Synthesis of6-O-(3,5,5-Trimethyl-n-Hexanoyl)-3',4'-O-Benzylidene-Chartreusin (AMixture of the Exo Form and the Endo Form at a Ratio of ˜1:1) (Referredto Hereinafter as Compound No. 236)

(1) In a mixture of 4.0 ml of anhydrous pyridine, 4.0 ml of anhydrouschloroform and 15 ml of anhydrous ethyl acetate was dissolved 700 mg ofthe 3',4'-O-isopropylidene-2",4"-O-di(tert-butyldimethylsilyl)-obtainedin Synthesis Example 10 above, after which 1,220 mg of3,5,5-trimethyl-n-hexanoic acid and 1,590 mg of dicyclohexylcarbodiimidewere added, and the resulting mixture was subjected to reaction withstirring at 25° C. for 100 hours.

After completion of the reaction, the reaction mixture was filtered andthe filtrate was concentrated under reduced pressure to obtain an oilysubstance.

The oily substance was purified by a silica gel column chromatographyand then dissolved in a mixture of 20 ml of tetrahydrofuran and 6 ml of3N hydrochloric acid, and the resulting mixture was subjected toreaction with stirring at 25° C. for 28 hours.

After completion of the reaction, the reaction mixture was neutralizedwith an aqueous sodium hydrogencarbonate solution and extracted withchloroform, after which the chloroform layer was dried and the solventwas removed by distillation under reduced pressure to obtain 271 mg ofyellow powder of 6-O-(3,5,5-trimethyl-m-hexanoyl)chartreusin(intermediate No. 551)

(2) The aforesaid powder (120 mg) was washed with ether and dissolved in5.0 ml of anhydrous chloroform, followed by adding thereto 1.5 ml ofbenzaldehyde dimethylacetal and 1 mg of p-toluenesulfonic acid, and theresulting mixture was subjected to reaction with stirring at 25° C. for8 hours.

After completion of the reaction, purification was conducted in the samemanner as in Synthesis Example 29 (2) above to obtain 52 mg of thedesired compound.

SYNTHESIS EXAMPLE 32 Synthesis of6-O-(n-Hexanoyl)-3',4'-O-Benzylidene-Chartreusin (A Mixture of the ExoForm and the Endo Form at a Ratio of ˜1:1) (Referred to Hereinafter asCompound No. 196)

(1) In a mixture of 0.2 ml of anhydrous pyridine and 5.0 ml of anhydrouschloroform was dissolved 572 mg of the3',4'-O-isopropylidene-2",4"-O-di(tert-butyldimethylsilyl)-chartreusin(intermediate No. 533) obtained in Synthesis Example 10 above, afterwhich 180 mg of n-hexanoyl chloride was added, and the resulting mixturewas subjected to reaction with stirring at 15° C. for 2 hours.

After completion of the reaction, an aqueous sodium hydrogencarbonatesolution was added and the resulting mixture was extracted withchloroform. The chloroform layer was washed with water and then with anaqueous sodium chloride solution and was dried, after which the solventwas removed by distillation under reduced pressure to obtain a oilysubstance.

The oily substance was purified by a silica gel column chromatographyand then dissolved in a mixture of 17 ml of tetrahydrofuran and 6 ml of3N hydrochloric acid, and the resulting solution was subjected toreaction with stirring at 30° C. for 48 hours.

After completion of the reaction, the reaction mixture was neutralizedwith an aqueous sodium hydrogen-carbonate solution and extracted withchloroform, after which the chloroform layer was dried and the solventwas removed by distillation under reduced pressure to obtain 342 mg ofyellow powder of 6-O-(n-hexanoyl)-chartreusin (intermediate No. 550).

(2) According to Synthesis Example 31 (2) above, 120 mg of the powderwas subjected to benzylidenation to obtain 77 mg of the desiredcompound.

SYNTHESIS EXAMPLE 33 Synthesis of6-O-Acetyl-3',4'-O-Isopropylidene-Chartreusin (Referred to Hereinafteras Compound No. 203)

(1) In 0.6 ml of anhydrous pyridine was dissolved 150 mg of the3',4'-O-isopropylidene-2",4"-O-di(tert-butyldimethylsilyl)-chartreusin(intermediate No. 533obtained in Synthesis Example 10 above, after which0.3 ml of acetic anhydride was added, and the resulting solution wassubjected to reaction with stirring at 25° C. for 6 hours.

After completion of the reaction, the reaction mixture was subjected topurification and acid treatment according to Synthesis Example 32 (1)above to obtain 60 mg of yellow powder of 6-O-acetyl-chartreusin(intermediate No. 548).

(2) According to Synthesis Example 28 (2) above, 30 mg of the powder wassubjected to acetonation to obtain 20 mg of the desired compound.

SYNTHESIS EXAMPLE 34 Synthesis of6-O-(3-Cyclohexene-1-Carbonyl)-3',4'-O-Isopropylidene-Chartreusin(Referred to Hereinafter as Compound No. 223)

(1) In a mixture of 1.7 ml of anhydrous pyridine and 1.7 ml of anhydrouschloroform was dissolved 150 mg of the3',4'-O-isopropylidene-2",4"-O-di(tert-butyldimetylsilyl)-chartreusin(intermediate No. 533) obtained in Synthesis Example 10 above, afterwhich 0.06 ml of 3-cyclohexene-1-carboxylic acid and 0.07 ml of thionylchloride were added, and the resulting mixture was subjected to reactionwith stirring at 0° C. for 0.2 hour.

After completion of the reaction, the reaction mixture was subjected topurification and acid treatment according to Synthesis Example 32 (1)above to obtain 123 mg of yellow powder of6-O-(3-cyclohexene-1-carbonyl)-chartreusin (intermediate No. 556).

(2) According to Synthesis Example 28 (2) above, 123 mg of the powderwas subjected to acetonation to obtain 66 mg of the desired compound.

The amino acid, the amino acid derivatives, the carboxylic acid and thecarboxylic acid derivatives of the general formula (VII) are easilyavailable or can be synthesized by a conventional process. Examples ofprocesses for the synthesis of these compounds which are used asmaterials for preparing compound No. 1 to compound No. 250 which arehereinafter mentioned are described below.

SYNTHESIS EXAMPLE 35 Synthesis of β-(1-Pyrrolidinyl)-Propionic Acid(Used for Preparing Compound No. 9 and Compound No. 34)

In 5 ml of absolute methanol were dissolved 500 mg of acrylic acid and800 mg of pyrrolidine, and the resulting solution was subjected toreaction with stirring at room temperature for 24 hours.

After completion of the reaction, the methanol and the unreactedpyrrolidine were removed under reduced pressure, after which water wasadded to the residue and the resulting aqueous solution was adjusted topH 9 to 10 with an aqueous sodium hydroxide solution. The aqueoussolution thus adjusted was washed with ethyl acetate and then adjustedto pH 1 to 2 with hydrochloric acid. The acidic aqueous solution thusobtained was washed with ethyl acetate and then adjusted to pH 6.0 againwith an aqueous sodium hydroxide solution. Subsequently, the weaklyacidic aqueous solution thus obtained was filtered, after which thefiltrate was concentrated under reduced pressure to remove water,whereby white powder was obtained. The white powder was dissolved in amixture of ethanol and a small amount of water, and the resultingsolution was filtered, after which the filtrate was concentrated underreduced pressure to obtain 280 mg of the desired compound.

NMR (60 MHz, δ values in CD₃ OD): 2.08 (4H, m, --CH₂ --CH₂ --), 2.54(2H, t, J=6 Hz, --COCH₂ --), ##STR30##

The following amino acid derivative was synthesized according toSynthesis Example 35 above:

β-Morpholino-propionic acid (used for preparing compound No. 32)

NMR (60 MHz, δ values in CD₃ OD): 2.45 (2H, t, J=6 Hz, --COCH₂ --)##STR31## 3.83 (4H, m, --CH₂ OCH₂ --)

SYNTHESIS EXAMPLE 36 Synthesis of N-Trifluoroacetyl-β-Amino-IsobutyricAcid (Used for Preparing Compound Nos. 12, 30, 37, 44 and 68)

To 2.0 ml of trifluoroacetic anhydride was added 300 mg ofβ-amino-isobutyric acid in small portions, and the resulting mixture wasstirred at 0° C. for 30 minutes and then subjected to reaction withstirring at room temperature for 3 hours.

After completion of the reaction, the unreacted trifluoroaceticanhydride was removed under reduced pressure, after which water wasadded to the residue and the resulting mixture was extracted with ethylacetate. The ethyl acetate layer obtained was washed with an aqueoussodium chloride solution, dried, and then concentrated under reducedpressure to obtain a white crude product. Subsequently, the crudeproduct was washed with a mixed solvent of hexane and ether and thendried to obtain 480 mg of the desired compound having a melting point of61.0°-65.0° C.

NMR (60 MHz, δ values in CDCl₃): 1.25 (3H, d, J=7 Hz, CH₃), 2.80 (1H, m,--CH--), 3.53 (2H, t, J=7 Hz, --CH₂ --N--), 7.47 (1H, m, --NH--), 10 97(1H, s, --COOH)

The following amino acid derivatives were synthesized according toSynthesis Example 36 above:

N-trifluoroacetyl-6-alanine (used for preparing compound Nos. 21, 28,31, 41, 49, 100 and 132) m.p. 115.0°-120.0° C.

N-trifluoroacetyl-β-amino-n-butyric acid (used for preparing compoundNos. 39, 51 and 94) m.p. 126.0°-130.0° C.

N-trifluoroacetyl-β-amino-n-caproic acid (used for preparing compoundNos. 97, 98 and 130) m.p. 88.0°-90.0° C.

N-trifluoroacetyl-8-amino-n-caprylic acid (used for preparing compoundNos. 64, 77 and 99) m.p. 58.0°-61.0° C.

N-trifluoroacetyl-5-amino-n-valeric acid (used for preparing compoundNo. 43) m.p. 89.0°-92.0° C.

N-methyl-N-trifluoroacetyl-glycine (used for preparing compound Nos. 25,67, 82 and 86)

NMR (60 MHz, δ values in CDCl₃): 3.22(3H, s, N--CH₃), 4.17(2H, s,--CO--CH₂ --N--), 10.47(1H, s, --COOH)

N-trifluoroacetyl-4-amino-n-butyric acid (used for preparing compoundNos. 24, 57 and 91)

NMR (60 MHz, δ values in CDCl₃): 2.00(2H, m, --CH₂ --), 2.32(2H, t, J=7Hz, --CO--CH₂ --), 3.22-3.62(2H, m, --CH₂ --N--)

N-trifluoroacetyl-2-amino-cyclohexanecarboxylic acid (used for preparingcompound Nos. 26, 27, 117 and 118)

NMR (60 MHz, δ values in CDCl₃) 1.14-2.17(8H, m, CH₂ ×4), 2.91(1H, m,--CH--CO--), 4.11(1H, m, --CH--N--)

SYNTHESIS EXAMPLE 37 Synthesis of N-trichloroacetyl-β-alanine (used forpreparing compound Nos. 22, 56 and 112)

To 5.6 ml of anhydrous chloroform was added 500 mg of β-alanine, and 1.3ml of trichloroacetyl chloride was dropped thereinto with stirring at 0°C. After completion of the dropping, the resulting mixture was subjectedto reaction with stirring at room temperature for 5 hours.

After completion of the reaction, water was added and the mixture thusobtained was extracted with ethyl acetate. The ethyl acetate layerobtained was washed with an aqueous sodium chloride solution and thenconcentrated to obtain an oily substance. The oily substance wasrecrystallized from a mixed solvent of ethyl acetate and hexane toobtain 270 mg of the desired compound having a melting point of102.0°-110.5° C.

The following amino acid derivative was synthesized according toSynthesis Example 37 above.

N-benzoyl-β-amino-isobutyric acid (used for preparing compound No. 13)

SYNTHESIS EXAMPLE 38 Synthesis of N-carbobenzyloxy-β-amino-isobutyricacid (used for preparing the compound No. 60)

In a mixture of 10 ml of pyridine and 10 ml of water was dissolved 500mg of β-amino-isobutyric acid, and 1.5 ml of benzyloxycarbonyl chloridewas dropped thereinto with stirring at 0° C. After completion of thedropping, the resulting mixture was stirred at room temperature for 3hours, after which the pyridine was removed under reduced pressure.Then, hydrochloric acid was added to the residue, and the resultingmixture was extracted with ethyl acetate. The ethyl acetate layerobtained was washed successively with diluted hydrochloric acid, waterand an aqueous sodium chloride solution, and then concentrated to obtainan oily substance. Subsequently, the oily substance was washed with amixed solvent of ether and hexane to obtain 380 mg of the desired com-pound.

NMR (60 MHz, δ values in CDCl₃): 1.17(3H, d, J=7 Hz, CH₃), 2.69(1H, m,--CH--), 3.36(2H, t, J=7 Hz, --CH₂ --N--), 5.11(2H, s, benzyl proton),7.30(5H, s, aromatic proton), 9.97(1H, s, --COOH)

The following amino acid derivatives were synthesized according toSynthesis Example 38 above:

N-carbobenzyloxy-6-amino-n-caproic acid (used for preparing compoundNos. 110, 111 and 119) m.p. 54.0°-56.0° C.

N-carbobenzyloxy-N-isopropyl-β-amino-isobutyric acid (used for preparingcompound No. 135)

NMR (60 MHz, δ values in CDCl₃): 1.10(3H×3, d, J=7 Hz, CH₃ ×3), 5.08(2H,s, benzyl proton), 7.25(5H, aromatic proton)

N-carbobenzyloxy-2-amino-cyclohexanecarboxylic acid (used for preparingcompound No. 62)

NMR (60 MHz, δ values in CDCl₃): 1.11-2.17(8H, m, CH₂ ×4), 2.34-2.91(1H,m, --CH--CO--), 3.84-4.27(1H, m, --CH--N<), 4.97-5.21(2H, benzylproton), 6.91(1H, s, --NH--CO--), 7.27(5H, s, aromatic proton),10.57(1H, s, --COOH)

SYNTHESIS EXAMPLE 39 Synthesis of N-carbobenzyloxy-α-isopropyl-β-alanine(used for preparing compound Nos. 70, 105 and 125)

(1) In 20 ml of absolute methanol was dissolved 520 mg of metallicsodium, and 2.12 g of ethyl cyanoacetate was added thereto with stirringat room temperature, after which 4.0 g of isopropyl iodide was addeddropwise over a period of 10 minutes. After completion of the dropwiseaddition, the resulting mixture was stirred at room temperature for 3hours, refluxed for 1 hour, subjected to a conventional post-treatment,and then distilled under reduced pressure to obtain 2.1 g of methylα-isopropylcyanoacetate.

NMR (60 MHz, δ value in CDCl₃): 1.10(3H, d, J=7 Hz, CH₃), 1.13(3H, d,J=7 Hz, CH₃), 2.37(1H, m, CH), 3.46(1H, d, J=6 Hz, CH), 3.81(3H, s,--COOCH₃)

(2) In 6.0 ml of acetic acid was dissolved 560 mg of the methylα-isopropyl-cyanoacetate obtained in (1) above, after which 0.15 ml ofconcentrated sulfuric acid and 50 mg of platinum oxide (Adams catalyst)were added, and the resulting mixture was sub]ected to catalyticreduction in a hydrogen stream at 3 to 4 atmospheres for 4 hours.

After completion of the reaction, the reaction mixture was filtered.Then, water was added to the filtrate and the resulting mixture wasconcentrated under reduced pressure, after which the acetic acid wasremoved to obtain an oily substance. Subsequently, the oily substancewas dissolved in water, and the resulting solution was neutralized withabout 0.1N barium hydroxide and then filtered, after which the filtratewas concentrated under reduced pressure to obtain 570 mg of crude methylester of α-isopropyl-β-alanine.

(3) The crude methyl ester of α-isopropyl-β-alanine obtained in (2)above was treated according to Synthesis Example 38 above to obtainmethyl ester of N-carbobenzyloxy-α-isopropyl-β-alanine.

NMR (60 MHz, δ values in CDCl₃): 0.94(3H×2, d, J=7 Hz, CH₃ ×2), 3.65(3H,s, --COOCH₃), 5.05(2H, s, benzyl proton), 7.28(5H s, aromatic proton)

(4) In a mixture of 18 ml of methanol and 2.7 ml of a 2N aqueouspotassium hydroxide solution was dissolved 450 mg of the methyl ester ofN-carbobenzyloxy-α-isopropyl-β-alanine obtained in (3) above, and theresulting solution was stirred at 40° to 50° C. for 5 hours.

After completion of the reaction, the reaction mixture was neutralizedwith hydrochloric acid, after which the methanol was removed underreduced pressure, and the residue was acidified with dilutedhydrochloric acid and then extracted with ethyl acetate. The ethylacetate layer was washed with water and then with an aqueous sodiumchloride solution, thereafter dried, and then concentrated under reducedpressure to obtain crude crystals. The crude crystals wererecrystallized from a mixture of ethyl acetate and hexane to obtain 310mg of the desired compound having a melting point of 75.5°-78.5° C.

NMR (60 MHz, δ values in CDCl₃): 0.96(3H×2, d, J=7 Hz, CH₃ ×2), 5.05(2H,s, benzyl proton), 7.26(5H, s, aromatic proton), 10.69(1H, s, --COOH)

SYNTHESIS EXAMPLE 40 Synthesis of 3-Chloropropionyloxyacetic Acid (Usedfor Preparing Compound No. 149)

In a mixture of 5.0 ml of anhydrous pyridine and 3.0 ml of anhydrouschloroform was dissolved 2.0 g of glycolic acid, and 2.5 ml of3-chloropropionyl chloride was added dropwise at 0° C. After completionof the dropwise addition, the resulting mixture was subjected toreaction with stirring at 30° to 35° C. for 2 hours.

After completion of the reaction, the reaction mixture was added to 300ml of a saturated aqueous sodium chloride solution, and the resultingmixture was extracted with ethyl acetate. The ethyl acetate layer wasdried, after which the solvent was removed by distillation under reducedpressure to obtain 2.8 g of the desired compound.

NMR (60 MHz, δ values in CDCl₃): 2.89(2H, t, J=6 Hz, --CH₂ --CO--),3.73(2H, t, J=6 Hz, --CH₂ --Cl), 4.66(2H, s, --O--CH₂ --CO--), 10.8(1H,s, --COOH

SYNTHESIS EXAMPLE 41 Synthesis of 3-Methylsulfinyl-Propionic Acid (Usedfor Preparing Compound Nos. 150 and 152)

In 50 ml of water was dissolved 5.4 g of sodium metaperiodate, and 3.0 gof 3-methylthiopropionic acid was added dropwise at 1° to 3° C. over aperiod of 20 minutes. After completion of the dropwise addition, theresulting mixture was subjected to reaction with stirring at 1° to 3° C.for 2 hours

After completion of the reaction, the reaction mixture was filtered andthe filtrate was concentrated under reduced pressure to obtain a solid.Subsequently, the solid was dissolved in 30 ml of ethanol, followed byadding thereto 3.0 g of anhydrous sodium sulfate, and the resultingmixture was stirred at room temperature for 2 hours, after which themixture was filtered and the filtrate was concentrated under reducedpressure to obtain 3.2 g of the desired product.

NMR (60 MHz, δ values in CD₃ OD): 2.63(3H, s, CH₃ SO--), 2.81 (2H, t,J=4 Hz, --CH₂ --CO--), 2.96(2H, t, J=4 Hz, --CH₂ --SO--)

SYNTHESIS EXAMPLE 42 Synthesis of N,N-Dimethyl-β-Amino-Isobutyric Acid(Used for Preparing Compound No. 1)

In 1.0 ml of water was dissolved 1.5 g of methyl malonate, after which1.26 g of a 50% aqueous dimethylamine solution and 0.96 ml of a 37%aqueous formaldehyde solution were added with stirring at 0° C., and theresulting mixture was stirred at 0° to 5° C. for 3 hours and then at 80°C. for 30 minutes.

After completion of the reaction, the solvent was removed under reducedpressure, after which anhydrous sodium sulfate was added to the residue,and the resulting mixture was extracted with methanol. The methanolsolution thus obtained was filtered and then concentrated under reducedpressure to obtain a white solid. The solid was recrystallized from amixture of methanol and acetone to obtain 610 mg of the desired compoundhaving a melting point of 169.0°-174.0° C.

NMR (60 MHz, δ values in D₂ O, internal standard; DSS): ##STR32##

The following amino acids were synthesized according to SynthesisExample 42 above:

N,N-dimethyl-2-ethyl-β-alanine (used for preparing compound No. 134)

NMR (60 MHz, δ values in CDCl₃): ##STR33##

N-isopropyl-β-amino-isobutyric acid (used for preparingN-carbobenzyloxy-N-isopropyl-β-aminoisobutyric acid) m.p. 175.5°-176.0°C.

SYNTHESIS EXAMPLE 43 Synthesis ofN-(N',N'-Dimethyl-Glycyl)-β-Amino-Isobutyric Acid (Used for PreparingCompound No. 4)

(1) In a mixture of 3.0 ml of dioxane and 3.0 ml of pyridine wasdissolved 103 mg of N,N-dimethylglycine and 117 mg of methylβ-amino-isobutyrate, followed by adding thereto 227 mg ofdicyclohexylcarbodiimide, and the resulting mixture was subjected toreaction with stirring at room temperature for 24 hours.

After completion of the reaction, the reaction mixture was filtered andthe filtrate was concentrated under reduced pressure, after which theconcentrate was dissolved in a small amount of water, and only thesoluble fraction was concentrated under reduced pressure and dissolvedin a small amount of methanol. Only the soluble fraction thus obtainedwas concentrated under reduced pressure to obtain 186 mg of crude methylN-(N',N'-dimethyl-glycyl)-β-amino-isobutyrate.

(2) In a mixture of 1.0 ml of methanol and 1.0 ml of a 1.2N aqueoussodium hydroxide solution was dissolved 186 mg of the methyl ester, andthe resulting solution was subjected to reaction with stirring at roomtemperature for 1 hour.

After completion of the reaction, the reaction mixture was neutralizedwith diluted hydrochloric acid and then subjected to post-treatment inthe same manner as in (1) above to obtain 211 mg of crudeN-(N',N'-dimethylglycyl)-β-amino-isobutyric acid.

The following amino acid derivative was synthesized according toSynthesis Example 43 above:

N-(N'-carbobenzyloxy-glycyl)-β-amino-isobutyric acid (used for preparingcompound No. 74)

NMR (60 MHz, δ values in CD₃ Cl₃ --CD₃ OD):

1.13(3H, d, J=7 Hz, CH₃), 5.05(2H, s, benzyl proton), 7.27(5H, aromaticproton)

Specific examples of the compounds included in this invention aredescribed in Table 5.

                                      TABLE 5                                     __________________________________________________________________________     ##STR34##                                                   (I)              Compound                                                 Melting              No.   X.sub.1                                                                          X.sub.2       Isomer.sup.(2)                                                                       Q.sup.(1)            Salt  point                                                                         (°C.)         __________________________________________________________________________    1     H  Phenyl        Exo                                                                                   ##STR35##           HCl   126.5-136.0          2     H  Phenyl        Exo                                                                                   ##STR36##           HCl   160.0-165.0          3     H  Phenyl        Exo                                                                                   ##STR37##           H.sub.3 PO.sub.4                                                                    152.0-156.0          4     H  Phenyl        Exo                                                                                   ##STR38##           HCl   160.5-163.0          5     H  Phenyl        Exo                                                                                   ##STR39##           HCl   --                   6     H  Phenyl        Exo                                                                                   ##STR40##           H.sub.3 PO.sub.4                                                                    152.0-158.0          7     H  Phenyl        Exo                                                                                   ##STR41##           HCl   --                   8     H  Phenyl        Exo                                                                                   ##STR42##           HCl   142.0-148.5          9     H  Phenyl        Exo    (CH.sub.2).sub.2(1-pyrrolidinyl)                                                                   HCl   154.5-160.0          10    H  Phenyl        Exo    (CH.sub.2).sub.2 NHCOCH.sub.2 NH.sub.2                                                             H.sub.3 PO.sub.4                                                                    152.5-158.0          11    H  Phenyl        Exo    CH.sub.2 NHCOCH.sub.2 NHCOCH.sub.2 NH.sub.2                                                        H.sub.3 PO.sub.4                                                                    176.0-184.5          12    H  Phenyl        Exo                                                                                   ##STR43##           --    163.0-173.0          13    H  Phenyl        Exo                                                                                   ##STR44##           --    158.0-167.0          14    H  m-Fluorophenyl                                                                              Exo                                                                                   ##STR45##           H.sub.3 PO.sub.4                                                                    160.0-164.0          15    H  m-Fluorophenyl                                                                              Exo                                                                                   ##STR46##           HCl   142.5-149.5          16    H  m-Fluorophenyl                                                                              Exo    (CH.sub.2).sub.2 NH.sub.2                                                                          H.sub.3 PO.sub.4                                                                    145.0-152.5          17    H  Phenyl        Exo    (CH.sub.2).sub.2 NH.sub.2                                                                          HCl   170.5-174.5          18    H  Phenyl        Exo    (CH.sub.2).sub.2 NH.sub.2                                                                          1/3 H.sub.3 PO.sub.4                                                                163.5-167.0          19    H  Phenyl        Exo    (CH.sub.2).sub.5 NH.sub.2                                                                          HCl   155.0-159.5          20    H  Phenyl        Exo    (CH.sub.2).sub.2 NHCHO                                                                             --    160.0-172.0          21    H  Phenyl        Exo    (CH.sub.2).sub.2 NHCOCF.sub.3                                                                      --    169.0-175.0          22    H  Phenyl        Exo    (CH.sub.2).sub.2 NHCOCCl.sub.                                                                      --    165.0-173.0          23    H  Phenyl        Exo    (CH.sub.2).sub.2 NHCO(phenyl)                                                                      --    160.0-165.0          24    H  Phenyl        Exo    (CH.sub.2).sub.3 NHCOCF.sub.3                                                                      --    172.0-185.0          25    H  Phenyl        Exo                                                                                   ##STR47##           --    165.0-174.0          26    H  Phenyl        Exo                                                                                   ##STR48##           --    162.0-171.0          27    H  m-Fluorophenyl                                                                              Exo                                                                                   ##STR49##           --    179.0-186.0          28    H  Phenyl        Endo   (CH.sub.2).sub.2 NHCOCF.sub.3                                                                      --    151.5-156.5          29    H  Phenyl        Endo   (CH.sub.2).sub.2 NHCOCH.sub.3                                                                      --    150.5-157.5          30    H  m-Trifluoromethylphenyl                                                                     Endo                                                                                  ##STR50##           --    144.0-150.0          31    H  m-Bromophenyl Endo   (CH.sub.2).sub.2 NHCOCF.sub.3                                                                      --    145.0-152.0          32    H  Phenyl        Exo                                                                                   ##STR51##           HCl   152.0-159.5          33    H  m-Fluorophenyl                                                                              Exo    (CH.sub.2).sub.2 NHCOCH.sub.2 NH.sub.2                                                             H.sub.3 PO.sub.4                                                                    154.5-164.0          34    H  m-Fluorophenyl                                                                              Exo    (CH.sub.2).sub.2(1-pyrrolidinyl)                                                                   H.sub.3 PO.sub.4                                                                    108.0-120.5          35    H  Phenyl        Exo                                                                                   ##STR52##           H.sub.3 PO.sub.4                                                                    153.0-160.0          36    H  Phenyl        Exo                                                                                   ##STR53##           H.sub.3 PO.sub.4                                                                    150.0-157.0          37    H  m-Fluorophenyl                                                                              Exo                                                                                   ##STR54##           --    169.5-175.0          38    H  Phenyl        Exo    (CH.sub.2).sub.2 NHCOCH.sub.3                                                                      --    162.0-176.0          39    H  Phenyl        Exo                                                                                   ##STR55##           --    184.0-193.0          40    H  Phenyl        Mixture (1:1)                                                                        (CH.sub.2).sub.2 NHCHO                                                                             --    162.0-169.5          41    H  Phenyl        Mixture (1:1)                                                                        (CH.sub.2).sub.2 NHCOCF.sub.3                                                                      --    158.0-163.0          42    CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2 NH.sub.2                                                                          HCl   162.0-167.0          43    H  Phenyl        Exo    (CH.sub. 2).sub.4 NHCOCF.sub.3                                                                     --    176.0-186.0          44    H  Phenyl        Endo                                                                                  ##STR56##           --    152.0-156.5          45    H  Phenyl        Endo   (CH.sub.2).sub.2 NHCHO                                                                             --    150.0-159.0          46    H  m-Fluorophenyl                                                                              Endo   (CH.sub.2).sub.2 NHCHO                                                                             --    157.0-167.0          47    H  m-Fluorophenyl                                                                              Endo   (CH.sub.2).sub.2 NHCO(phenyl)                                                                      --    156.0-165.0          48    CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2 NHCHO                                                                             --    160.0-162.0          49    CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2 NHCOCF.sub.3                                                                      --    155.0-159.0          50    CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2 NHCO(phenyl)                                                                      --    146.0-149.0          51    CH.sub.3                                                                         CH.sub.3      --                                                                                    ##STR57##           --    157.5-164.5          52    H  m-Trifluoromethylphenyl                                                                     Endo   (CH.sub.2).sub.2 NHCHO                                                                             --    160.0-167.0          53    H  m-Trifluoromethylphenyl                                                                     Endo   (CH.sub.2).sub.2 NHCOCH.sub.3                                                                      --    149.0-153.0          54    H  m-Bromophenyl Endo   (CH.sub.2).sub.2 NHCHO                                                                             --    160.0-166.0          55    H  o-Methylphenyl                                                                              Exo    (CH.sub.2 ).sub.2 NHCHO                                                                            --    159.0-165.0          56    H  m-Bromophenyl Endo   (CH.sub.2).sub.2 NHCOCCl.sub.3                                                                     --    148.0-156.0          57    H  p-Fluorophenyl                                                                              Endo   (CH.sub.2).sub.3 NHCOCF.sub.3                                                                      --    150.5-156.0          58    H  o-Chlorophenyl                                                                              Endo   (CH.sub.2).sub.2 NHCHO                                                                             --    164.0-168.0          59    CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.5 NH.sub.2                                                                          CH.sub.3 COOH                                                                       152.5-159.0          60    H  m-Fluorophenyl                                                                              Exo                                                                                   ##STR58##           --    175.0-184.0          61    H  m-Fluorophenyl                                                                              Exo    (CH.sub.2).sub.2 NHCOCH.sub.2 NHCOOCH.sub.2                                   (phenyl)             --    143.0-148.0          62    H  Phenyl        Exo                                                                                   ##STR59##           --    156.0-165.0          63    CH.sub.3                                                                         CH.sub.3      --                                                                                    ##STR60##           --    140.0-144.0          64    H  m-Fluorophenyl                                                                              Endo   (CH.sub.2).sub.7 NHCOCF.sub.3                                                                      --    113.0-120.0          65    H  Phenyl        Endo   (CH.sub.2).sub.2 NHCO(phenyl)                                                                      --    148.5-157.0          66    H  Phenyl        Endo                                                                                  ##STR61##           --    156.0-164.5          67    H  Phenyl        Endo                                                                                  ##STR62##           --    156.5-164.0          68    H  m-Fluorophenyl                                                                              Endo                                                                                  ##STR63##           --    145.0-154.0          69    H  Phenyl        Exo                                                                                   ##STR64##           --    160.0-167.0          70    H  Phenyl        Exo                                                                                   ##STR65##           --    175.0-185.0          71    H  Phenyl        Exo    CH.sub.2 NHCOOCH.sub.2 (phenyl)                                                                    --    176.0-183.0          72    H  Phenyl        Exo    (CH.sub.2).sub.2 NHCOOCH.sub.2 (phenyl)                                                            --    155.5-165.0          73    H  m-Fluorophenyl                                                                              Exo    (CH.sub.2).sub.2 NHCOOCH.sub.2 (phenyl)                                                            --    152.0-161.0          74    H  Phenyl        Exo                                                                                   ##STR66##           --    129.5-139.0          75    H  Phenyl        Exo                                                                                   ##STR67##           --    148.0-153.0          76    H  Phenyl        Exo    (CH.sub.2).sub.3 NHCOOCH.sub.2 (phenyl)                                                            --    156.0-167.0          77    H  Phenyl        Exo    (CH.sub.2).sub.7 NHCOCF.sub.3                                                                      --    173.0-181.0          78    H  Phenyl        Mixture (1:1)                                                                        (CH.sub.2).sub.5 NHCOCF.sub.3                                                                      --    143.0-149.0          79    H  Phenyl        Exo                                                                                   ##STR68##           --    165.0-176.0          80    H  Phenyl        Endo   (CH.sub.2).sub.2 NH.sub.2                                                                          HCl   166.5-170.0          81    H  3-Thienyl     Exo    (CH.sub.2).sub.2 NHCHO                                                                             --    171.0-180.0          82    H  o-Fluorophenyl                                                                              Mixture (1:5)                                                                         ##STR69##           --    157.5-167.0          83    H  2-Phenylethyl Exo    (CH.sub.2).sub.2 NHCHO                                                                             --    160.0-172.0          84    H  2-Furyl       Mixture (1:1)                                                                        (CH.sub.2).sub.2 NHCHO                                                                             --    160.0-169.0          85    CH.sub.3                                                                         CH.sub.3      --                                                                                    ##STR70##           --    147.5-153.0          86    CH.sub.3                                                                         CH.sub.3      --                                                                                    ##STR71##           --    174.0-180.0          87    CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2 NHCOCH.sub.3                                                                      --    153.0-156.5          88    CH.sub.3                                                                         CH.sub.3      --     CH.sub.2 NHCO(phenyl)                                                                              --    160.5-164.0          89    H  3-Thienyl     Endo   (CH.sub.2).sub.2 NHCHO                                                                             --    172.0-177.0          90    H  m-Chlorophenyl                                                                              Exo    (CH.sub.2).sub.2 NHCHO                                                                             --    170.0-179.0          91    H  p-Fluorophenyl                                                                              Exo    (CH.sub.2).sub.3 NHCOCF.sub.3                                                                      --    188.5-196.0          92    H  p-Fluorophenyl                                                                              Exo    (CH.sub.2).sub.2 NHCHO                                                                             --    183.5-189.5          93    H  2,4-Dichlorophenyl                                                                          Endo   (CH.sub.2).sub.2 NHCHO                                                                             --    175.0-182.0          94    H  o-Chlorophenyl                                                                              Endo                                                                                  ##STR72##           --    162.0-165.0          95    H  p-Methoxyphenyl                                                                             Exo    (CH.sub.2).sub.2 NHCHO                                                                             --    165.0-173.0          96    H  p-Methoxyphenyl                                                                             Exo    (CH.sub.2).sub.2 NHCO(phenyl)                                                                      --    174.0-182.0          97    H  p-Fluorophenyl                                                                              Exo    (CH.sub.2).sub.5 NHCOCF.sub.3                                                                      --    188.0-193.0          98    CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.5 NHCOCF.sub.3                                                                      --    193.0-197.5          99    CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.7 NHCOCF.sub.3                                                                      --    167.0-173.5          100   H  CH.sub.2 CH.sub.3                                                                           --     (CH.sub.2).sub.2 NHCOCF.sub.3                                                                      --    145.0-153.5          101   H  m-Trifluoromethylphenyl                                                                     Endo                                                                                  ##STR73##           --    155.0-164.0          102   CH.sub.3                                                                         CH.sub.3      --                                                                                    ##STR74##           --    153.0-161.0          103   H  Phenyl        Endo   (CH.sub.2).sub.2 NHCOOCH.sub.2 (phenyl)                                                            --    132.0-140.0          104   H  Phenyl        Endo   CH.sub.2 NHCOOCH.sub.2 (phenyl)                                                                    --    150.0-154.0          105   H  o-Chlorophenyl                                                                              Endo                                                                                  ##STR75##           --    152.0-159.0          106   H  Phenyl        Exo                                                                                   ##STR76##           --    182.0-189.0          107   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2 NHCOOCH.sub.2 (phenyl)                                                            --    133.0-137.5          108   CH.sub.3                                                                         CH.sub.3      --     CH.sub.2 NHCOOCH.sub.2 (phenyl)                                                                    --    149.5-152.0          109   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.3 NHCOOCH.sub.                                                                      --(phenyl)                                                                          146.0-151.0          110   H  Phenyl        Endo   (CH.sub.2).sub.5 NHCOOCH.sub.2 (phenyl)                                                            --    114.5-122.5          111   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.5 NHCOOCH.sub.2 (phenyl)                                                            --    149.5-152.5          112   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2 NHCOCCl.sub.3                                                                     --    159.0-163.5          113   H  Pentafluorophenyl                                                                           Endo   (CH.sub.2).sub.2 NHCHO                                                                             --    164.0-172.0          114   H  Phenyl        Exo                                                                                   ##STR77##           --    162.0-182.0          115   H  Phenyl        Exo                                                                                   ##STR78##           --    140.0-147.0          116   H  m-Fluorophenyl                                                                              Exo                                                                                   ##STR79##           --    174.0-182.0          117   H  m-Fluorophenyl                                                                              Exo                                                                                   ##STR80##           --    185.0-194.0          118   H  Phenyl        Exo                                                                                   ##STR81##           --    176.0- 185.0         119   H  Phenyl        Exo    (CH.sub.2).sub.5 NHCOOCH.sub.2 (phenyl)                                                            --    178.0-186.0          120   H  m-Nitrophenyl Endo   (CH.sub.2).sub.2 NHCHO                                                                             --    158.0-165.0          121   H  Phenyl        Exo                                                                                   ##STR82##           --    165.0-173.0          122   H  Phenyl        Exo                                                                                   ##STR83##           --    195.0-202.0          123   H  p-Bromophenyl Exo    (CH.sub.2).sub.2 NHCO(phenyl)                                                                      --    168.5-173.0          124   H  p-Bromophenyl Endo   (CH.sub.2).sub.2 NHCO(phenyl)                                                                      --    164.5-170.0          125   CH.sub.3                                                                         CH.sub.3      --                                                                                    ##STR84##           --    148.0-152.0          126   CH.sub.3                                                                         CH.sub.3      --                                                                                    ##STR85##           --    164.0-167.5          127   H  p-Chlorophenyl                                                                              Endo                                                                                  ##STR86##           --    155.0-164.0          128   CH.sub.3                                                                         CH.sub.3      --                                                                                    ##STR87##           --    164.0-166.0          129   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.11 NHCOCH.sub.3                                                                     --    182.0-187.5          130   H  CH.sub.2 COCH.sub.3                                                                         --     (CH.sub.2).sub.5 NHCOCF.sub.3                                                                      --    138.5-146.0          131   CH.sub.3                                                                         CH.sub.2 CH.sub.3                                                                           --                                                                                    ##STR88##           --    148.0-155.0          132   (CH.sub.2).sub.5 --     (CH.sub.2).sub.2 NHCOCF.sub.3                                                                      --    151.5-156.0          133   (CH.sub.2).sub.5 --                                                                                    ##STR89##           --    158.0-165.0          134   H  Phenyl        Exo                                                                                   ##STR90##           HCl   153.5-160.0          135   H  Phenyl        Exo                                                                                   ##STR91##           --    202.0-209.5          136   H  Phenyl        Exo    (CH.sub.2).sub. 2 NHCOCH.sub.2 NH.sub.2                                                            HCl   173.0-184.0          137   H  Phenyl        Exo                                                                                   ##STR92##           HCl   164.0-172.0          138   H  Phenyl        Exo                                                                                   ##STR93##           HCl   185.0-195.0          139   H  Phenyl        Exo    (CH.sub.2).sub.2 N(CH.sub.3).sub.2                                                                 HCl   163.5-167.0          140   H  Phenyl        Exo                                                                                   ##STR94##           HCl   --                   141   H  Phenyl        Exo                                                                                   ##STR95##           --    --                   142   H  Phenyl        Exo    (CH.sub.2).sub.2 NHCH.sub.3                                                                        HCl   169.0-173.0          143   H  Phenyl        Exo                                                                                   ##STR96##           --    175.0-178.0          144   H  Phenyl        Exo                                                                                   ##STR97##           --    --                   145   H  m-Fluorophenyl                                                                              Exo                                                                                   ##STR98##           --    --                   146   H  m-Fluorophenyl                                                                              Exo    (CH.sub.2).sub.2 NHCO(phenyl)OCH.sub.3                                                             --)   --                   147   H  Phenyl        Exo    (CH.sub.2).sub.3 OH  --    171.0-181.0          148   H  Phenyl        Exo    CH.sub.2 OCOCH.sub.3 --    156.0-163.0          149   H  Phenyl        Exo    CH.sub.2 OCOCH.sub.2 CH.sub.2 Cl                                                                   --    150.0-158.0          150   H  Phenyl        Exo    (CH.sub.2).sub.2 SOCH.sub.3                                                                        --    170.0-180.0          151   H  Phenyl        Exo                                                                                   ##STR99##           --    190.0-200.0          152   H  Phenyl        Exo    (CH.sub.2).sub.2 SCH.sub.3                                                                         --    169.0-174.0          153   H  Phenyl        Exo    (CH.sub.2).sub.2 COCH.sub.3                                                                        --    178.0-186.0          154   H  Phenyl        Exo    (CH.sub.2).sub.2 (phenyl)                                                                          --    187.0-194.0          155   H  3-Thienyl     Exo    (cyclopropyl)        --    172.0-180.0          156   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2 COCH.sub.3                                                                        --    170.0-182.0          157   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2 Cl  --    164.0-170.0          158   H  m-Fluorophenyl                                                                              Endo   (phenyl)N(CH.sub.3).sub.2 (m)                                                                      --    181.0-189.0          159   H  p-Fluorophenyl                                                                              Exo    CH.sub.2 CH(CH.sub.3).sub.2                                                                        --    163.0-173.0          160   H  m-Nitrophenyl Endo   (CH.sub.2).sub.2 CHCH.sub.2                                                                        --    146.0-154.0          161   H  m-Trifluoromethylphenyl                                                                     Endo   C(CH.sub.3)CHCH.sub.3 (E)                                                                          --    148.0-158.0          162   H  m-Trifluoromethylphenyl                                                                     Endo   (CH.sub.2).sub.2 COCH.sub.3                                                                        --    142.0-150.0          163   H  m-Bromophenyl Endo   CH.sub.2 CH(CH.sub.3).sub.2                                                                        --    148.0-158.0          164   H  Phenyl        Exo    (CH.sub.2).sub.2 Cl  --    170.0-176.0          165   H  Phenyl        Exo    (CH.sub.2).sub.3 OCH.sub.2 (phenyl)                                                                --    184.0-188.0          166   H  Phenyl        Exo    (CH.sub.2).sub.2 NO.sub.2                                                                          --    164.5-171.0          167   H  Phenyl        Exo    CH.sub.2 OCO(phenyl) --    186.0-196.0          168   H  Phenyl        Exo    (CH.sub.2).sub.2 SO.sub.2 CH.sub.3                                                                 --    179.0-191.0          169   H  Phenyl        Exo    CH.sub.2 CH(CH.sub.3).sub.2                                                                        --    194.0-204.0          170   H  Phenyl        Exo    (CH.sub.3).sub.3     --    214.0-217.0          171   CH.sub.3                                                                         CH.sub.3      --     CH.sub.2 CH(CH.sub.3).sub.2                                                                        --    213.0-225.0          172   CH.sub.3                                                                         CH.sub.3      --                                                                                    ##STR100##          --    163.0-169.0          173   CH.sub.3                                                                         CH.sub.3      --     C(CH.sub.3)CHCH.sub.3 (E)                                                                          --    169.0-175.0          174   CH.sub.3                                                                         CH.sub.3      --     CH.sub.2 S(phenyl)   --    145.0-153.0          175   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2 CHCH.sub.2                                                                        --    210.0-215.0          176   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2 OCH.sub.2 CH.sub.3                                                                --    148.0-158.0          177   CH.sub.3                                                                         CH.sub.3      --     (cyclopropyl)        --    174.0-181.0          178   CH.sub.3                                                                         CH.sub.3      --     (cyclopropyl)CH.sub.3 (2)                                                                          --    166.0-176.0          179   CH.sub.3                                                                         CH.sub.3      --     (phenyl)Br(p)        --    208.0-218.0          180   CH.sub.3                                                                         CH.sub.3      --     (phenyl)Cl.sub.2 (2,4)                                                                             --    168.0-176.0          181   CH.sub.3                                                                         CH.sub.3      --     (phenyl)Cl(o)        --    173.0-181.0          182   CH.sub.3                                                                         CH.sub.3      --     (phenyl)CF.sub.3 (p) --    180.0-188.0          183   CH.sub.3                                                                         CH.sub.3      --     (phenyl)CN(p)        --    189.0-198.0          184   CH.sub.3                                                                         CH.sub.3      --     (phenyl)OCH.sub.3 (m)                                                                              --    168.0-180.0          185   CH.sub.3                                                                         CH.sub.3      --     (phenyl)Cl(p)        --    183.0-190.0          186   H  Phenyl        Endo   (phenyl)NO.sub.2 (p) --    191.0-197.0          187   H  o-Chlorophenyl                                                                              Endo   (phenyl)CN(p)        --    187.0-194.0          188   H  m-Chlorophenyl                                                                              Endo   (CH.sub.2).sub.2 OCH.sub.2 CH.sub.3                                                                --    133.0-142.0          189   H  m-Nitrophenyl Endo   (phenyl)Cl(o)        --    167.0-180.0          190   H  p-Chlorophenyl                                                                              Endo   (cyclopropyl)CH.sub.3 (2)                                                                          --    174.0-180.0          191   H  Phenyl        Exo    (CH.sub.2).sub.2 CH.sub.3                                                                          --    178.0-188.0          192   H  Phenyl        Exo    (CH.sub.2).sub.2 CHCH.sub.2                                                                        --    186.0-194.0          193   H  Phenyl        Exo    (phenyl)OCH.sub.3 (m)                                                                              --    178.0-183.0          194   H  Phenyl        Exo    (phenyl)Cl(p)        --    190.0-202.0          195   H  Phenyl        Exo    (phenyl)CF.sub.3 (p) --    227.0-233.0          196   H  Phenyl        Mixture (1:1)                                                                        (CH.sub.2).sub.4 CH.sub.3                                                                          --    145.0-154.0          197   CH.sub.3                                                                         CH.sub.3      --     CHCH.sub.2           --    166.0-174.0          198   CH.sub.3                                                                         CH.sub.3      --                                                                                    ##STR101##          --    170.0-190.0          199   CH.sub. 3                                                                        CH.sub.3      --     CH.sub.2 OCO(phenyl) --    158.0-168.0          200   CH.sub.3                                                                         CH.sub.3      --     CHCHCH.sub.3 (E)     --    172.0-181.0          201   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2 CCH --    155.0-163.0          202   CH.sub.3                                                                         CH.sub.3      --     CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3                                                                --    148.0-155.0          203   CH.sub.3                                                                         CH.sub.3      --     CH.sub.3             --    184.0-190.0          204   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.3 Cl  --    205.0-213.0          205   CH.sub.3                                                                         CH.sub.3      --     CH.sub.2 O(phenyl)   --    193.0-203.0          206   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2 CO(phenyl)F(p)                                                                    --    153.0-161.0          207   CH.sub.3                                                                         CH.sub.3      --     (phenyl)CO.sub.2 CH.sub.3 (p)                                                                      --    180.0-188.0          208   CH.sub.3                                                                         CH.sub.3      --     (phenyl)OCH.sub.3 (p)                                                                              --    202.0-212.0          209   CH.sub.3                                                                         CH.sub.3      --     (phenyl)N(CH.sub.3).sub.2 (m)                                                                      --    176.0-186.0          210   H  o-Fluorophenyl                                                                              Mixture (1:5)                                                                        (CH.sub.2).sub.2 Cl  --    161.0-171.0          211   H  2-Furyl       Mixture (1:1)                                                                        (phenyl)CO.sub.2 CH.sub.3 (p)                                                                      --    190.0-199.0          212   H  Phenyl        Endo   (CH.sub.2).sub.2 CH.sub.3                                                                          --    158.0-168.0          213   H  Phenyl        Endo   (CH.sub.2).sub.2 CHCH.sub.2                                                                        --    152.0-160.0          214   H  Phenyl        Endo   (CH.sub.2).sub.3 Cl  --    153.0-162.0          215   H  Phenyl        Endo   C(CH.sub.3)CHCH.sub.3 (E)                                                                          --    172.0-179.0          216   H  o-Methoxyphenyl                                                                             Exo    (CH.sub.2).sub.2 CH.sub.3                                                                          --    167.0-178.0          217   H  2,4-Dichlorophenyl                                                                          Endo   (CH.sub.2).sub.2 CHCH.sub.2                                                                        --    140.0-150.0          218   H  2-Phenylethyl Exo    (phenyl)OCH.sub.3 (m)                                                                              --    148.0-158.0          219   H  CH.sub.2 CH.sub.3                                                                           --                                                                                    ##STR102##          --    168.0-176.0          220   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.3).sub.8 CH.sub.3                                                                          --    209.0-212.0          221   (CH.sub.2).sub.5 --     CHCHCH.sub.3 (E)     --    167.0-174.0          222   CH.sub.3                                                                         CH.sub.3       --    CH(CH.sub.3).sub.2   --    178.0-190.0          223   CH.sub.3                                                                         CH.sub.3      --                                                                                    ##STR103##          --    170.0-180.0          224   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2 CO(phenyl)                                                                        --    158.0-165.0          225   CH.sub.3                                                                         CH.sub.3      --     CH.sub.2 O(phenyl)F(p)                                                                             --    194.0-202.0          226   CH.sub.3                                                                         CH.sub.3      --     (phenyl)Cl(m)        --    173.0-181.0          227   H  Phenyl        Endo   CH.sub.2 CH(CH.sub.3).sub.2                                                                        --    157.0-165.0          228   H  2-Furyl       Mixture (1:1)                                                                        (CH.sub.2).sub.2 CH.sub.3                                                                          --    175.0-181.0          229   H  Phenyl        Endo   (phenyl)Br(p)        --    195.0-205.0          230   H  Phenyl        Endo   (cyclopropyl)        --    176.0-182.0          231   H  Phenyl        Exo    C(CH.sub.3)CHCH.sub.3 (E)                                                                          --    182.0-188.0          232   H  Phenyl        Exo    (cyclopropyl)        --    180.0-185.0          233   H  2-Phenylethyl Exo    (cyclopropyl)        --    159.0-165.0          234   H  p-Methoxyphenyl                                                                             Exo    C(CH.sub.3)CHCH.sub.3 (E)                                                                          --    210.0-215.0          235   CH.sub.3                                                                         CH.sub.3      --      (CH.sub.2).sub.5 Br --    219.0-225.0          236   H  Phenyl        Mixture (1:1)                                                                         ##STR104##          --    175.0-195.0          237   CH.sub.3                                                                         CH.sub.3      --                                                                                    ##STR105##          --    210.0-220.0          238   CH.sub.3                                                                         CH.sub.3      --     CHCHCHCHCH.sub.3     --    176.0-184.0          239   CH.sub.3                                                                         CH.sub.3      --                                                                                    ##STR106##          --    172.0-177.0          240   CH.sub.3                                                                         CH.sub.3      --     (CH.sub.2).sub.2(cyclohexyl)                                                                       --    228.0-234.0          241   (CH.sub.2).sub.5 --                                                                                    ##STR107##          --    158.0-165.0          242   CH.sub.3                                                                         CH.sub.3      --     (phenyl)             --    221.0-226.0          243   CH.sub.3                                                                         CH.sub.3      --     COCH.sub.3           --    --                   244   CH.sub.3                                                                         CH.sub.3      --     COOCH(CH.sub.3).sub.2                                                                              --    --                   245   CH.sub.3                                                                         CH.sub.3      --     (cyclopentyl)        --    --                   246   H  Phenyl        Exo    (CH.sub.2).sub.2 COO(phenyl)                                                                       --    --                   247   H  Phenyl        Exo    CH.sub.2 CH.sub.2 CN --    --                   248   H  2-(3-Methylthienyl)                                                                         Exo    (CH.sub.2).sub.2 COCH.sub.3                                                                        --    --                   249   H  2-(3-Bromothienyl)                                                                          Exo                                                                                   ##STR108##          --    --                   250   H  2-(5-Methylfuryl)                                                                           Exo    (CH.sub.2).sub.2 COCH.sub.3                                                                        --    --                   __________________________________________________________________________     Note:                                                                         .sup.(1) The symbol (p) in (CH.sub.2).sub.2 NHCO(phenyl)OCH.sub.3 (p) of      compound No. 146 indicates that the phenyl nucleus is substituted by          OCH.sub.3 in the pposition. The symbol (2) in (cyclopropyl)CH.sub.3 (2) o     compound No. 178 indicates that the cyclopropyl is substituted by CH.sub.     in the 2position. The other symbols are interpreted according to the          above. The symbol (E) denotes Entgegen.                                       Note:                                                                         .sup.(2) In the mixture, the ratio is that of exo form to endo form.     

Next, NMR data of typical compounds of the abovementioned compounds ofthis invention are shown below.

Compound No. 12

NMR (60 MHz, δ values in CDCl₃): 1.30(3H, d, J=7 Hz, CH₃), 1.48(3Hx2, d,J=7 Hz, CH₃ x2), 2.87(3H, s, Ar--CH₃), 3.37(3H, s, O--CH₃), 5.26(1H, d,J=8 Hz, anomer proton), 5.89(1H, d, J=4 Hz, anomer prokton), ##STR109##

7.17-8.10(10H, aromatic proton)

Compound No. 13

NMR (60 MHz, δ values in CDCl₃): 1.33(3H, d, J=7 Hz, CH₃), 1.47(3Hx2, d,J=7 Hz CH₃ x2), 2.81(3H, s, Ar--CH₃), 3.37(3H, s, O--CH₃), 5.30(1H, d,J=8 Hz, anomer proton), 5.92 (1H, d, J=4 Hz, anomer proton), ##STR110##7.07-8.20 (15H, aromatic proton)

Compound No. 20

NMR (60, MHz δ values in CDCl₃ --CD₃ OD): 1.30(3H, d, J=7 Hz, CH₃),1.50(3H, d, J=7 Hz, CH₃), 2.86(3H, s, Ar--CH₃), 3.38(3H, s, O--CH₃),5.39(1H, d, J=8 Hz, anomer proton), 5.95(1H, d, J=4 Hz, anomer proton),##STR111## 7.27-8.16 (10H, aromatic proton), 8.18(1H, s, formyl proton)

Compound No. 21

NMR (60 MHz, δ values in CDCl₃ --CD₃ OD): 1.28(3H, d, J=7 Hz, CH₃),1.50(3H, d, J=7 Hz, CH₃), 2.89(3H, s, Ar--CH₃), 3.41(3H, s, O--CH₃),5.40(1H, d, J=8 Hz, anomer proton), 5.90(1H, d, J=4 Hz, anomer proton),##STR112## 7.17-8.00 (10H, aromatic proton)

Compound No. 23

NMR (60 MHz, δ values in CDCl₃) 1.32(3H, d, J=7 Hz, CH₃), 1.48(3H, d,J=7 Hz, CH₃), 2.91(3H, s, Ar--CH₃), 3.43(3H, s, O--CH₃), 5.34(1H, d, J=8Hz, anomer proton), 6.00(1H, d. J=4 Hz, anomer proton), ##STR113##7.17-8.27 (15H, aromatic proton)

Compound No. 24

NMR (60 MHz, δ values in CDCl₃ --Cd₃ OD): 1.30(3H, d, J=7 Hz, CH₃),1.50(3H, d, J=7 Hz, CH₃), 2.87(3H, s, Ar--CH₃), 3.40(3H, s, O--CH₃),5.37(1H, d, J=8 Hz, anomer proton), 5.9l(1H, d, J=4 Hz, anomer proton),##STR114## 7.17-8.00 (10H aromatic proton)

Compound No. 25

NMR (60 MHz, δ values in CDCl₃): 1.3(3H, d, J=7 Hz, CH₃), 1.49(3H, d,J=7 Hz, CH₃), 2.87(3H, s, Ar--CH₃), 3.39(3H, s, O--CH₃), 3.42(3H, s,N--CH₃), 5.29(1H, d, J=8 Hz, anomer proton), 5.93(1H, d, J=4 Hz anomerproton), ##STR115## 7.17-8.17(10H, aromatic proton)

Compound No. 26

NMR (60 MHz, δ values in CDCl₃) 1.30(3H, d, J=7 Hz, CH₃), 1.48(3H, d,J=7 Hz, CH₃), 1.60-2.10(8H, m, cyclohexyl portion), 2.91(3H, s,Ar--CH₃), 3.41(3H, s, O--CH₃), 5.30(1H, d, J=8 Hz, anomer proton),5.94(1H, d, J=4 Hz, anomer proton), ##STR116## 7.17-7.93(10H, aromaticproton)

Compound No. 27

NMR (60 MHz, δ values in CDCl₃): 1.31(3H, d, J=7 Hz, CH₃), 1.48(3H, d,J=7 Hz, CH₃), 1.58-1.98(8H, m, cyclohexyl portion), 2.90(3H, s,Ar--CH₃), 3.40(3H, s, O--CH₃), 5.28(1H, d, J=8 Hz, anomer proton),5.91(1H, d, J=4 Hz, anomer proton), ##STR117## 7.00-7.91(9H, aromaticproton)

Compound No. 28

NMR (60 MHz, δ values in CDCl₃ --CD₃ OD): 1.06(3H, d, J=7 Hz, CH₃),1.48(3H, d, J=7 Hz, CH₃), 2.87(3H, s, Ar--CH₃), 3.40(3H, s, O--CH₃),5.38(1H, d, J=8 Hz, anomer proton), 5.80(1H, d, J=4 Hz, anomer proton),##STR118## 7.17-8.23(10H, aromatic proton)

Compound No. 29

NMR (60 MHz, δ values in CDCl₃ --CD₃ O: 1.05(3H, d, J=7 Hz, CH₃),1.47(3H, d, J=7 Hz, CH₃), 2.02(3H, s, N--Ac), 2.85(3H, s, Ar--CH₃),3.37(3H, s, O--CH ), 5.34(1H, d, J=8 Hz, anomer proton), 5.77(1H, d, J=4Hz, anomer proton), ##STR119## 7.21-8.04(10 H, aromatic proton)

Compound No. 30

NMR (60 MHz, δ values in CDCl₃): 1.12(3H, d, J=7 Hz, CH₃), 1.47(3Hx2, d,J=7 Hz, CH₃ x2), 2.81(3H, s, Ar--CH₃), 3.37(3H, s, O--CH₃), 5.33(1H, d,J=8 Hz, anomer proton), 5.77(1H, d, J=4 Hz, anomer proton), ##STR120##7.20-8.27(9H, aromatic proton)

Compound No. 31

NMR (60 MHz, δ values in CDCl₃): 1.19(3H, d, J=7 Hz, CH₃), 1.51(3H, d,J=7 Hz, CH₃), 2.90(3H, s, Ar--CH₃), 3.48(3H, s, O--CH₃), 5.46(1H, d, J=8Hz, anomer proton), 5.86(1H, d, J=4 Hz, anomer proton) ##STR121##7.25-8.02 (9H, aromatic proton)

Compound No. 37

NMR (60 MHz, δ values in CDCl₃) 1.30(3H, d, J=7 Hz, CH₃), 1.47(3H, d,J=7 Hz, CH₃), 1.53(3H, d, J=7 Hz, CH₃), 2.88(3H, s, Ar--CH₃), 3.39(3H,s, O--CH₃), 5.28(1H, d, J=8 Hz, anomer proton), 5.91(1H, d, J=4 Hz,anomer proton), ##STR122## 7.00-8.17(9H, aromatic proton)

Compound No. 38

NMR (60 MHz, δ values om CDCl₃ --CD₃ OD): 1.29(3H, d, J=7 Hz, CH₃),1.48(3H, d, J=7 Hz, CH₃), 2.02(3H, s, N--Ac), 2.84(3H, s, Ar--CH₃),3.34(3H, s, O--CH₃), 5.32(1H, d, J=8 Hz, anomer proton), 5.85(1H, J=8Hz, anomer proton), ##STR123## 7.14-8.10(10H, aromatic proton)

Compound No. 39

NMR (60 MHz, δ values in CDCl₃): 1.35(3H, d, J=7 Hz, CH₃), 1.52(3H, d,J=7 Hz, CH₃), 1.58(3H, d, J=7 Hz, CH₃), 2.96(3H, s, Ar--CH₃), 3.48(3H,s, O--CH₃), 5.35(1H, d, J=8 Hz, anomer proton), 6.00(1H, d, J=4 Hz,anomer proton), ##STR124## 7.25-8.17(10H, aromatic proton)

Compound No. 40

NMR (60 MHz, δ values in CDCl₃ --CD₃ OD): 1.05(3Hx1/2, d, J=7 Hz, CH₃),1.30(3Hx1/2, d, J=7 Hz, CH₃), 1.50(3H, d, J=7 Hz, CH₃), 2.92(3H, s,Ar--CH₃), 3.43(3H, s, O--CH₃), 5.42(1H, m, anomer proton), 5.97(1H, m,anomer proton), ##STR125## 7.27-7.93 (10H, aromatic proton), 8.20(1H, s,formyl proton), (a diastereomer mixture of benzylidene)

Compound No. 41

NMR (60 MHz, δ values in CDCl₃) 1 .10(3Hx1/2, d, J=7 Hz, CH₃),1.32(3Hx1/2, d, J=7 Hz, CH₃), 1.50(3H, d, J=7 Hz, CH₃), 2.88(3H, s,Ar--CH₃), 3.40(3H, s, O--CH₃), 5.28(1H, m, anomer proton), 5.87(1H, m,anomer proton), ##STR126## 7.23-7.93(10H, aromatic proton) (adiastereomer mixture of benzylidene)

Compound No. 43

NMR (60 MHz δ values in CDCl₃ --CD₃ OD): 1.29(3H, d, J=7 Hz, CH₃),1.47(3H, d, J=7 Hz, CH₃), 1.61-2.01(4H, m, CH₂ x2), 2.79(3H, s,Ar--CH₃), 3.36(3H, s, O--CH₃), 5.32(1H, d, J=8 Hz, anomer proton),5.91(1H, d, J=4 Hz, anomer proton), ##STR127## 7.21-8.21(10H, aromaticproton)

Compound No. 44

NMR (60 MHz, δ values in CDCl₃): 1.09(3H, d, J=7 Hz, CH₃), 1.48(6H, d,J=7 Hz, CH₃ x2), 2.83(3H, s, Ar--CH₃), 3.37(3H, s, O--CH₃), 5.29(1H, d,J=8 Hz, anomer proton), 5.77(1H, d, J=4 Hz, anomer proton), ##STR128##7.17-7.92 (10H, aromatic proton)

Compound No. 45

NMR (60 MHz, δ values in CDCl₃ -CD₃ OD): 1.05(3H, d, J=7 Hz, CH₃),1.48(3H, d, J=7 Hz, CH₃), 2.87(b 3H, s, Ar--CH₃), 3.40(3H, s, O--CH₃),5.38(1H, d, J=8 Hz, anomer proton), 5.80(1H, d, J=4 Hz, anomer proton),##STR129## 7.23-7.93 (10H, aromatic proton), 8.13(1H, s, formyl proton)

Compound No. 46

NMR (60 MHz, δ values in CDCl₃) 1.12(3H, d, J=7 Hz, CH₃), 1.45(3H, d,J=7 Hz, CH₃), 2.79(3H, s, Ar--CH₃), 3.38(3H, s, O--CH₃), 5.34(1H, d, J=8Hz, anomer proton), 5.74(1H, d, J=4 Hz, anomer proton), ##STR130##7.07-8.04 (9H, aromatic proton), 8.08(1H, s, formyl proton):

Compound No. 47

NMR (60 MHz, δ values in CDCl₃): 1.15(3H, d, J=7 Hz, CH₃), 1.45(3H, d,J=7 Hz, CH₃), 2.79(3H, s, Ar--CH₃), 3.37(3H, s, O--CH₃), 5.32(1H, d, J=8Hz, anomer proton), 5.76(1H, d, J=4 Hz, anomer proton), ##STR131##6.93-8.00 (14H, aromatic proton)

Compound No. 48

NMR (60 MHz, δ values in CDCl₃): 1.23-1.80(12H, CH₃ x4), 2.80(3H, s,Ar--CH₃), 3.38(3H, s, O--CH₃), 5.20(1H, m, anomer proton), 5.83(1H, m,anomer proton), 7.23-8.20(5H, aromatic proton), 8.17(1H, formyl proton)

Compound No. 49

NMR (60 MHz, δ values in CDCl₃): 1.23-1.83(12H, CH₃ x4), 2.83(3H, s,Ar--CH₃), 3.40(3H, s, O--CH₃), 5.20(1H, m, anomer proton), 5.83(1H, m,anomer proton), 7.27-8.03(5H, aromatic proton)

Compound No. 50

NMR (60 MHz, δ values in CDCl₃): 1.28-1.87(12H, CH₃ x4), 2.83(3H, s,Ar--CH₃), 3.38(3H, s, O--CH₃), 5.17(1H, m, anomer proton), 5.83(1H, m,anomer proton), 7.23-8.20(10H, aromatic proton)

Compound No. 51

NMR (60 MHz, δ values in CDCl₃ --CD₃ OD): 1.27-1.83(15H, CH₃ x5),2.85(3H, s, Ar--CH₃), 3.37(3H, s, O--CH₃), 5.27(1H, m, anomer proton),5.82(1H, m, anomer proton), 7.23-8.00(5H, aromatic proton)

Compound No. 52

NMR (60 MHz, δ values in CDCl₃): 1.10(3H, d, J=7 Hz, CH₃), 1.45(3H, d,J=7 Hz, CH₃), 2.75(3H, s, Ar--CH₃), 3.34(3H, s, O--CH₃), 5.27(1H, d, J=8Hz, anomer proton), 5.67(1H, d, J=4 Hz, anomer proton), ##STR132##7.06-8.16 (9H, aromatic proton), 8.02(1H, s, formyl proton)

Compound No. 53

NMR (60 MHz, δ values in CDCl₃): 1.13(3H, d, J=7 Hz, CH₃), 1.47(3H, d,J=7 Hz, CH₃), 1.99(3H, s, N--Ac), 2.79(3H, s, Ar--CH₃), 3.39(3H, s,O--CH₃), 5.34(1H, d, J=8 Hz, anomer proton), 5.73(1H, d, J=4 Hz, anomerproton), ##STR133## 7.09-8.22(9H, aromatic proton)

Compound No. 54

NMR (60 MHz, δ values in CDCl₃) 1.15(3H, d, J=7 Hz, CH₃), 1.44(3H, d,J=7 Hz, CH₃), 2.76(3H, s, Ar--CH₃), 3.35(3H, s, O--CH₃), 5.28(1H, d, J=8Hz , anomer proton), 5.68(1H, d, J=4 Hz, anomer proton), ##STR134##6.95-8.00(9H, aromatic proton), 8.03(1H, s, formyl proton)

Compound No. 55

NMR (60 MHz, δ values in CDCl₃ --CD₃ OD): 1.24(3H, d, J=7 Hz, CH₃),1.42(3H, d, J=7 Hz, CH₃), 2.45(3H, s, Ar--CH₃), 2.77(3H, s, Ar--CH₃),3.33(3H, s, O--CH₃), 5.24(1H, d, J=8 Hz, anomer proton), 5.81(1H, d, J=4Hz, anomer proton), ##STR135## 6.90-8.17(9H, aromatic proton), 8.00(1H,s, formyl proton)

Compound No. 56

NMR (60 MHz, δ values in CDCl₃): 1.16(3H, d, J=7 Hz, CH₃), 1.48(3H, d,J=7 Hz, CH₃), 2.84(3H, s, Ar--CH₃), 3.40(3H, s, O--CH₃), 5.37(1H, d, J=8Hz, anomer proton),5.77(1H, d, J=4 Hz, anomer proton), ##STR136##7.11-8.11(9H, aromatic proton)

Compound No. 57

NMR (60 MHz, δ values in CDCl₃): 1.11(3H, d, J=7 Hz, CH₃), 1.47(3H, d,J=7 Hz, CH₃), 2.85(3H, s, Ar--CH₃), 3.39(3H, s, O--CH₃), 5.34(1H, d, J=8Hz, anomer proton), 5.78(1H, d, J=4 Hz, anomer proton), ##STR137##6.95-8.21(9H, aromatic proton)

Compound No. 58

NMR (60 MHz, δ values in CDCl₃) 1.09(3H, d, J=7 Hz, CH₃), 1.52(3H, d,J=7 Hz, CH₃), 2.87(3H, s, Ar--CH₃), 3. 46(3H, s, O--CH₃), 5.41 (1H, d,J=8 Hz, anomer proton), 5.86(1H, d, J=4 Hz, anomer proton), ##STR138##7.2-8.4 (9H, aromatic proton), 8.42(1H, s, formyl proton)

Compound No. 60

NMR (60 MHz, δ values in CDCl₃): 1.31(3H, d, J=7 Hz, CH₃), 1.48(3Hx 2,d, J=7 Hz, CH₃ ×2), 2.86(3H, s, A--CH₃), 3.39(3H, s, O--CH₃), 5.13(2H,s, benzyl proton), 5.29(1H, d, J=8 Hz, anomer proton), 5.94(1H, d, J=4Hz, anomer proton), ##STR139## 7.24-7.97(14H, aromatic proton)

Compound No. 61

NMR (60MHz, δ values in CDCl₃): 1.32(3H, d, J=7 Hz, CH₃), 1.45(3H,)=7Hz, CH₃), 2.76(3H, s, Ar--CH₃), 3.37(3H, s, O--CH₃), 5.06(2H, s,benzyl proton), 5.32(1H, d, J=8 Hz, anomer proton), 5.89(1H, d, J=4 Hz,anoer proton), ##STR140## 6.93-7.90(1H, aromatic proton)

Compound No. 62

NMR (60 MHz, δ values in CDCl₃): 1.28(3H, d, J=7 Hz, CH₃ ), 1.45(3H, d,J=7 Hz, CH₃), 1.50-2.10 (8H, m, cyclohexyl portion), 2.86(3H, s,Ar--CH₃), 3.37(3H, s, O--CH₃), 5.08(2H, s, benzyl proton), 5.22(1H, d,J=8 Hz, anomer proton), 5.84(1H, d, J=4 Hz, anomer proton), ##STR141##7.17-8.10(15H, aromatic proton)

Compound No. 63

NMR (60 MHz, δ values in CDCl₃): 1.20-1.80(14H, CH₃ x 4, CH₂ x1),2.17(3H, s, S--CH₃), 2.87(3H, s, Ar--CH₃), 3.42(3H, s, O--CH₃), 5.20(3H,m, benzyl proton+anomer proton), 5.85(1H, m, anomer proton),7.20-8.20(10H, aromatic proton)

Compound No. 64

NMR (60 MHz, 6 values in CDC ₃) 1.13(3H, d, J=7 Hz, CH₃), 1.27-1.93(13H,m, CH₃ x1, CH₂ x5), 2.81(3H, s, Ar--CH₃), 3.40(3H, s, O--CH₃), 5.33(1H,d, J=8 Hz, anomer proton), 5.76(1H, d, J=4 HZ, anomer proton),##STR142## 7.00-8.93(9H, aromatic proton)

Compound No. 135

NMR (60 MHz, δ values in CDCl₃): 1.03-1.69(3Hx5, CH₃ x ), 2.87(3H, s,Ar--CH₃), 3.41(3H, s, O--CH₃), 5.21(2H, s, benzyl proton), 5.32(1H, d,J=8Hz, anomer proton), 5.93(1H, d, J=4Hz, anomer proton), ##STR143##7.13-8.00(15H, aromatic proton)

Compound No. 147

NMR (60 MHz, δ values in CDCl₃): 1.30(3H, d, J=7 Hz, CH₃), 1.46(3H, d,J=7 Hz, CH₃), 2.87(3H, s, Ar--CH₃), 3.40(3H, s, O--CH₃), 5.28(1H, d, J=8Hz, anomer proton), 5.91(1H, d, J=4 Hz, anomer proton), ##STR144##6.90-8.33(10H, aromatic proton)

Compound No. 148

NMR (60 MHz, δ values in CDCl₃ --CD₃ OD): 1.30(3H, d, J=7 Hz, CH₃),1.48(3H, d, J=7 Hz, CH₃), 2.25(3H, s, -OAc), 2.91(3H, s, Ar--CH₃),3.40(3H, s, O--CH₃), 5.17(2H, s, -CO--CH₂ -O--), 5.36(1H, d, J=8 Hz,anomer proton), 5.92(1H, d, J=4 Hz, anomer [6 37(1H, s, -O--H-O--)7.30-8.07(10H, proton), ##STR145## 7.30-8.07(10H, aromatic proton)

Compound No. 149

NMR (60 MHz, δ values in CDCl₃): 1.31(3H, d, J=7 Hz, CH₃), 1.48(3H, d,J=7 Hz, CH₃), 2.87(3H, s, Ar--CH₃), 3.39(3H, s, O--CH₃), 5.13-6.17(4H,anomer proton x2, -CO--CH₂ -O--), ##STR146## 7.20-8.20(10H, aromaticproton)

Compound No. 150

NMR (60 MHz, δ values in CDCl₃): 1.31(3H, d, J=7 Hz, CH₃), 1.49(3H, d,J=7 Hz, CH₃), 2.67(3H, s, -SO--CH₃), 2.87(3H, s, Ar--CH₃), 3.40(3H, s,O--CH₃), 5.28(1H, d, J=8 Hz, anomer proton), 5.92(1H, d, J=4 Hz, anomerproton), ##STR147## 7.25-8.08(10H, aromatic proton)

Compound No. 151

NMR (60 MHz, δ values in CDCl₃): 1.30(3H, d, J=7 Hz, CH₃), 1.49(3H, d,J=7 Hz, CH₃), 1.81(3H, d, J=7 Hz, CH₃), 2.86(3H, s, Ar--CH₃), 3.40(3H,s, O--CH₃), 5.29(1H, d, J=8 Hz, anomer proton), 5.92(1H, d, J=4 Hz,anomer proton) ##STR148## 7.25-7.96(15H, aromatic proton)

Compound No. 152

NMR (60 MHz, δ values in CDCl₃): 1.31(3H, d, J=7 Hz, CH₃), 1.47(3H, d,J=7 Hz, CH₃), 2.24(3H, s, --S--CH₃), 2.87(3H, s, Ar--CH₃), 3.38(3H, s,O--CH₃), 5.27(1H, d, J=8 Hz, anomer proton), 5.91(1H, d, J=4 Hz, anomerproton), ##STR149## 7.10-8.26(10H, aromatic proton)

Compound No. 153

NMR (60 MHz, δ values in CDCl₃): 1.28(3H, d, J=7 Hz, CH₃), 1.46(3H, d,J=7 Hz, CH₃), 2.20(3H, s, --CO--CH₃), 2.81(3H, s, Ar--CH₃), 3.35(3H, s,O--CH₃), 5.25(1H, d, J=8 Hz, anomer proton), 5.87(1H, d, J=4 Hz, anomerproton), ##STR150## 7.17-8.13(10H, aromatic proton)

Compound No. 154

NMR (60 MHz, δ values in CDCl₃ --CD₃ OD): 1.28(3H, d, J=7 Hz, CH₃),1.49(3H, d, J=7 Hz, CH₃), 2.86(3H, s, Ar--CH₃), 3.39(3H, s, O--CH₃),5.40(1H, d, J=8 Hz, anomer proton), 5.92l1H, d, J=4 Hz, anomer proton),##STR151## 7.07-7.90(15H, aromatic proton)

Compound No. 155

NMR (60 MHz, δ values in CDCl₃): 0.75-1.63(10H, CH₃ x2, CH₂ x2),2.84(3H, s, Ar--CH₃), 3.39(3H, s, O--CH₃), 5.28(1H, d, J=8 Hz, anomerproton), 5.88(1H, d, J=4 Hz, anomer proton), ##STR152## 6.94-8.07 (8H,thienyl group and aromatic proton)

Compound No. 156

NMR (60 MHz, δ values in CDCl₃): 1.16-1.85(3Hx4, CH₃ x4), 2.26(3H, s,--COCH₃), 2.86(3H, s, Ar--CH₃), 3.41(3H, s, --OCH₃), 5.13-5.39 (1H,anomer proton), 5.86(1H, d, J=4 Hz, anomer proton), 7.23-8.23(5H,aromatic proton)

Compound No. 157

NMR (60 MHz, δ values in CDCl₃): 1.16-1.92(3Hx4, CH₃ x4), 2.89(3H, s,Ar--CH₃), 3.45(3H, s, O--CH₃), 5.27(1H, d, J=8 Hz, anomer proton),5.89(1H, d, J=4 Hz, anomer proton), 7.32-8.26(5H, aromatic proton)

Compound No. 158

NMR (60 MHz, δ values in CDCl₃ --CD₃ OD): 1.11 (3H, d, J=7 Hz, CH₃),1.46(3H, d, J=7 Hz, CH₃), 2.85(3H, s, Ar--CH₃), ##STR153## 3.39(3H, s,O--CH₃), 5.40(1H, d, J=8 Hz, anomer proton), 5.77(1H, d, J=4 Hz, anomerproton), ##STR154## 6.87-8.13(13H, aromatic proton)

Compound No. 159

NMR (60 MHz, δ values in CDCl₃ --CD₃ OD): 1.14(3Hx2, d, J=7 Hz, CH₃ x2),1.26(3H, d, J=7 Hz, CH₃), 1.45(3H, d, J=7 Hz, CH₃), 2.83(3H, s,Ar--CH₃), 3.37(3H, s, O--CH₃), 5.30(1H, d, J=8 Hz, anomer proton),5.83(1H, d, J=4 Hz, anomer proton), ##STR155## 6.86-7.92(9H, aromaticproton)

Compound No. 160

NMR (60 MHz, δ values in CDCl₃): 1.14(3H, d, J=7 Hz, CH₃), 1.46(3H, d,J=7 Hz, CH₃), 2.77(3H, s, Ar--CH₃), 3.39(3H, s, O--CH₃), 4.96-5.83(5H,anomer proton x2, --CH═CH₂), ##STR156## 7.23-8.66(9H, aromatic proton)

Compound No. 161

NMR (60 MHz, δ values in CDCl₃): 1.12(3H, d, J=7 Hz, CH₃), 1.46(3H, d,J=7 Hz, CH₃), 1.83-2.49(8H, CH₃ x2, --OHx2), 2.82(3H, s, Ar--CH₃),3.40(3H, s, O--CH₃), 5.40(1H, d, J=8 Hz, anomer proton), 5.77(1H, d, J=4Hz, anomer proton), ##STR157## 6.85-8.30(10H, vinyl proton x1, aromaticproton x9)

Compound No. 162

NMR (60 MHz, δ values in CDCl₃): 1.10(3H, d, J=7 Hz, CH₃), 1.45(3H, d,J=7 Hz, CH₃), 2.21(3H, s, --CO--CH₃), 2.82(3H, s, Ar--CH₃), 3.37(3H, s,O--CH₃), 5.30(1H, d, J=8 Hz, anomer proton), 5.72(1H, d, J=4 Hz, anomerproton), ##STR158## 7.20-8.23(9H, aromatic proton)

Compound No. 163

NMR (60 MHz, δ values in CDCl₃): 0.89-1.76(3Hx4, CH₃ x4), 2.79(3H, s,Ar--CH₃), 3.43(3H, s, O--CH₃), 5.33(1H, d, J=8 Hz, anomer proton),5.69(1H, d, J=4 Hz, anomer proton), ##STR159## 7.17-7.92(9H, aromaticproton)

Compound No. 164

NMR (60 MHz, δ values in CDCl₃): 1.31(3H, d, J=7 Hz, CH₃), 1.48(3H, d,J=7 Hz, CH₃), 2.88(3H, s, Ar--CH₃), 3.40(3H, s, O--CH₃), 5.31(1H, d, J=8Hz, anomer proton), 5.92(1H, d, J=8 Hz, anomer proton), ##STR160##7.15-8.15(10H, aromatic proton)

Compound No. 165

NMR (60 MHz, δ values in CDCl₃): 1.30(3H, d, J=7 Hz, CH₃), 1.46(3H, d,J=7 Hz, CH₃), 2.84(3H, s, Ar--CH₃), 3.37(3H, s, O--CH₃), 4.53(2H, s,benzyl proton), 5.25(1H, d, J=8 Hz, anomer proton), 5.88(1H, d, J=4 Hz,anomer proton), ##STR161## 7.17-8.00(15H, aromatic proton)

Compound No. 166

NMR (60 MHz, δ values in CDCl₃): 1.31(3H, d, J=7 Hz, CH₃), 1.47(3H, d,J=7 Hz, CH₃), 2.90(3H, s, Ar--CH₃), 3.41(3H, s, O--CH₃), 5.28(1H, d, J=8Hz, anomer proton), 5.92(1H, d, J=4 Hz, anomer proton), ##STR162##7.18-8.15(10H, aromatic proton)

Compound No. 167

NMR (60 MHz, δ values in CDCl₃): 1.30(3H, d, J=7 Hz, CH₃), 1.46(3H, d,J=7 Hz, CH₃), 2.84(3H, s, Ar--CH₃), 3.36(3H, s, O--CH₃), 5.29(1H, d, J=8Hz, anomer proton), 5.91(1H, d, J=4 Hz, anomer proton), ##STR163##7.15-8.45 (15H, aromatic proton)

Compound No. 168

NMR (60 MHz, δ values in CDCl₃ -CD₃ OD): 1.30(3H, d, J=7 Hz, CH₃),1.48(3H, d, J=7 Hz, CH₃), 2.89(3H, s, Ar--13 CH₃), 3.04(3.04(3H, s,--SO₂ --CH₃), 13.37(3H, s, O--CH₃), 5.10-6.10(2H, anomer proton x2),##STR164## 7.30-8.27(10H, aromatic proton)

Compound No. 169

NMR (60 MHz, δ values in CDCl₃): 1.17(3Hx2, d, J=7 Hz, CH₃ x2), 1.32(3H,d, J=7 Hz, CH₃), 1.50(3H, d, J=7 Hz, CH₃), 2.92(3H, s, Ar--CH₃),3.46(3H, s, O--CH₃), 5.33(1H, d, J=8 Hz, anomer proton), 5.96(1H, d, J=4Hz, anomer proton), ##STR165## 7.29-8.06(10H, aromatic proton)

Compound No. 170

NMR (60 MHz, δ values in CDCl₃ --CD₃ OD): 1.29(3H, d, J=7 Hz, CH₃),1.46(3H, d, J=7 Hz, CH₃), 1.56(3Hx3, s, CH₃ x3), 2.86(3H, s, Ar--CH₃),3.39 (3H, s, O--CH₃), 5.31(1H, d, J=8 Hz, anomer proton), 5.90(1H, d,J=4 Hz, anomer proton), ##STR166## 7.17-8.10(10H, aromatic proton)

Compound No. 171

NMR (60 MHz, δ values in CDCl₃): 0.94-1.91(19H, CH₃ x6, CHx1), 2.87(3H,s, Ar--CH₃), 3.40(3H, s, O--CH₃), 5.21(1H, d, J=8Hz, anomer proton),5.85(1H, d, J=4 Hz, anomer proton), 7.15-7.97 (5H, aromatic proton)

Compound No. 172

NMR (60 MHz, δ values in CDCl₃): 1.10-1.86(3Hx6, CH₃ x6), 2.80(3H, s,Ar--CH₃), 3.37(3H, s, O--CH₃), 5.10-5.93(2H, anomer proton x2),7.17-8.26(5H, aromatic proton)

Compound No. 173

NMR (60 MHz, δ values in CDCl₃): 1.19-2.39(20H, CH₃ x6, --OHx2),2.84(3H, s, Ar--CH₃), 3.39(3H, s, O--CH₃), 5.22(1H, d, J=8 Hz, anomerproton), 5.84(1H, d, J=4 Hz, anomer proton), 7.00-8.00(6H, >C═CH--,aromatic proton x5)

Compound No. 174

NMR (60 MHz, δ values in CDCl₃): 1.13-1.79(3Hx4, CH₃ x4), 2.79(3H, s,Ar--CH₃), 3.34(3H, s, O--CH₃), 4.10(2H, s, --CO--CH₂ --S--), 5.13(1H, d,J=8 Hz, anomer proton), 5.73(1H, d, J=4 Hz, anomer proton),6.96-7.63(10H, aromatic proton)

Compound No. 175

NMR (60 MHz, δ values in CDCl₃): 1.13-1.92(3Hx4, CH₃ x4), 2.83(3H, s,Ar--CH₃), 3.40(3H, s, O--CH₃), 4.83-6.00(5H, m, anomer proton x2,--CH═CH₂), 7.20-8.00(5H, aromatic proton)

Compound No. 176

NMR (60 MHz, δ values in CDCl₃): 1.00-1.79(3Hx5, CH₃ x5), 2.84(3H, s,Ar--CH₃), 3.40(3H, s, --OCH₃), 5.23(1H, d, J=8 Hz, anomer proton),5.86(1H, d, J=4 Hz, anomer proton), 7.17-8.13(5H, aromatic proton)

Compound No. 177

NMR (60 MHz, δ values in CDCl₃): 0.70-1.87(3Hx4, 2Hx2, CH₃ x4,--CH₂,--CH₂ --), 2.84(3H, s, Ar--CH₃), 3.38(3H, s, O--CH₃), 5.20(1H, d,J=8 Hz, anomer proton), 5.83(1H, d, J=4 Hz, anomer proton),7.10-8.07(5H, aromatic proton)

Compound No. 178

NMR (60 MHz, δ values in CDCl₃): 0.66-1.93(18H, CH₃ x5, CH₂ x1, CHx1),2.83(3H, s, Ar--CH₃), 3.37(3H, s, O--CH₃), 5.15(1H, d, J=8 Hz, anomerproton), 5.78(1H, d, J=4 Hz, anomer proton), 7.16-8.00(5H, aromaticproton)

Compound No. 179

NMR (60 MHz, δ values in CDCl₃): 1.15-1.95(3Hx4, CH₃ x4), 2.87(3H, s,Ar--CH₃), 3.41(3H, s, O--CH₃), 5.22(1H, d, J=8 Hz, anomer proton),5.86(1H, d, J=4 Hz, anomer proton), 7.17-8.33(9H, aromatic proton)

Compound No. 180

NMR (60 MHz, δ values in CDCl₃): 1.11-1.87(3Hx4, CH₃ x4), 2.86(3H, s,Ar--CH₃), 3.39(3H, s, O--CH₃), 5.21(1H, d, J=8 Hz, anomer proton),5.85(1H, d, J=4 Hz, anomer proton), 7.27-8.57(8H, aromatic proton)

Compound No. 181

NMR (60 MHz, δ values in CDCl₃): 1.08-1.84(3Hx4, CH₃ x4), 2.85(3H, s,Ar--CH₃), 3.40(3H, s, O--CH₃), 5.23(1H, d, J=8 Hz, anomer proton),5.86(1H, d, J=4 Hz, anomer proton), 7.29-8.56(9H, aromatic proton)

Compound No. 182

NMR (60 MHz, δ values in CDCl₃): 1.08-1.87(3Hx4, CH₃ x4), 2.89(3H, s,Ar--CH₃), 3.43(3H, s, O--CH₃), 5.28(1H, d, J=8 Hz, anomer proton),5.94(1H, d, J=4 Hz, anomer proton), 7.30-8.70(9H, armatic proton)

Compound No. 183

NMR (60 MHz, δ values in CDCl₃):

1.24-1.86(3Hx4, CH₃ x4), 2.86(3H, s, Ar--CH₃), 3.40(3H, s, O--CH₃),5.24(1H, d, J=8 Hz, anomer proton), 5.88(1H, d, J=4 Hz, anomer proton),7.32-8.56(9H, aromatic proton)

Compound No. 184

NMR (60 MHz, δ values in CDCl₃):

1.17-1.87(3Hx4, CH₃ x4), 2.87(3H, s, Ar--CH₃), 3.39(3H, s, O--CH₃),3.86(3H, s, Ar--OCH₃), 5.03-5.36(1H, anomer proton), 5.70-6.03(1H,anomer proton), 7.07-8.20(9H, aromatic proton)

Compound No. 185

NMR (60 MHz, δ values in CDCl₃): 1.10-1.87(3Hx4, CH₃ x4), 2.88(3H, s,Ar--CH₃), 3.40(3H, s, O--CH₃), 5.24(1H, d, J=8 Hz, anomer proton),5.87(1H, d, J=4 Hz, anomer proton), 7.20-8.47(9H, aromatic proton)

Compound No. 186

NMR (60 MHz, δ values in CDCl₃): 1.10(3H, d, J=7 Hz, CH₃), 1.50(3H, d,J=7 Hz, CH₃), 2.86(3H, s, Ar--CH₃), 3.40(3H, s, O--CH₃), 5.35(1H, d, =8Hz, anomer proton), 5.82(1H, d, J=4 Hz, anomer proton), ##STR167##7.23-8.73 (14H, aromatic proton)

Compound No. 187

NMR (60 MHz, δ values in CDCl₃): 1.09(3H, d, J=7 Hz, CH₃), 1.51(3H, d,J=7 Hz, CH₃), 2.87(3H, s, Ar--CH₃), 3.40(3H, s, O--CH₃), 5.33(1H, d, J=8Hz, anomer proton), 5.77(1H, d, J=4 Hz, anomer proton), ##STR168##7.17-8.57(13H, aromatic proton)

Compound No. 188

NMR (60 MHz, δ values in CDCl₃): 1.14(3H, d, J=7Hz, CH₃), 1.28(3H, t,J=7Hz, CH₃), 1.47(3H, d, J=7Hz, CH₃), 2.82(3H, s, Ar--CH₃), 3.39(3H, s,O--CH₃), 5.34(1H, d, J=8Hz, anomer proton), 5.74(1H, d, J=4Hz, anomerproton), ##STR169## 7.2-8.18(9H, aromatic proton)

Compound No. 189

NMR (60MHz, δ values in CDCl₃): 1.16(3H, d, J=7Hz, CH₃), 1.49(3H, d,J=7Hz, CH₃), 2.83(3H, s, Ar--CH₃), 3.38(3H, s, O--CH₃), 5.37(1H, d,J=8Hz, anomer proton), 5.72(1H, d, J=4Hz, anomer proton), ##STR170##7.24-8.57(13H, aromatic proton)

Compound No. 190

NMR (60MHz, δ values in CDCl₃): 1.13(3H, d, J=7Hz, CH₃), 1.37-1.23(3H,CH₃), 1.45(3H, d, J=7Hz, CH₃), 2.85(3H, s, Ar--CH₃), 3.38(3H, s,O--CH₃), 5.32(1H, d, J=8Hz, anomer proton), 5.72(1H, d, J=4Hz, anomerproton), ##STR171## 7.17-8.13(9H, aromatic proton)

As shown in the experimental examples hereinafter described, thecompounds of this invention have excellent effects on P-388 leukemiacells.

The antitumor activity, acute toxicity, dose and administration routesof the compounds of this invention are described below.

(1) Antitumor Activity

Into BDF₁ mice were inoculated intraperitoneally P-388 leukemia cells ata rate of 1×10⁶ cells/mouse, and each drug to be tested was administeredintravenously on the first, fifth and ninth days after the inoculation.Whether the mice were alive or dead was observed for 30 days, and theratio of medium survival time of test and control animals (T/C) of eachtreatment group was calculated, taking the survival period of a controlgroup to which physiological saline was administered as 100. The resultsobtained are shown in Table 6. The drugs were as follows solutionsprepared by adding physiological saline to each of compound Nos. 8, 9,10, 11, 17, 34, 42, 59, 80 and 134; suspensions prepared by dispersingeach of compound Nos. 41, 78, 98, 100, 130, 191, 212, 213, 215, 227 and230 to 232 and a small amount of sodium carboxymethyl cellulose (Na.CMC)in physiological saline, and suspensions or solutions of each of theother compounds plus a small amount of a surface active agent (e.g.,Tween-80) in physiological saline.

                  TABLE 6                                                         ______________________________________                                        Compound No. Dose.sup.(1) (mg/kg)                                                                      T/C (%) of MST.sup.(2)                               ______________________________________                                        1            b           138                                                               c           214                                                  2            b           184                                                               c           216                                                  3            b           150                                                               c           192                                                  4            b           184                                                               c           216                                                  6            b           182                                                               c           242                                                  8            b           186                                                               c           220                                                  9            b           165                                                               c           292                                                  10           b           161                                                               c           197                                                  11           b           186                                                  12           b           203                                                               c           241                                                  13           b           186                                                               c           262                                                  14           b           195                                                  15           b           189                                                  16           b           164                                                               c           242                                                  17           b           206                                                               c           241                                                  18           b           196                                                               c           238                                                  19           b           184                                                               c           233                                                  20           b           203                                                               c           248                                                  21           b           210                                                               c           229                                                  22           b           181                                                  23           b           205                                                               c           233                                                  24           b           161                                                               c           223                                                  25           b           212                                                  26           b           195                                                               c           220                                                  27           b           179                                                  28           f           193                                                               h           227                                                  29           c           173                                                               f           221                                                  30           c           171                                                               f           257                                                  31           c           171                                                               f           238                                                  32           a           146                                                               b           186                                                  33           a           157                                                               b           186                                                  34           c           140                                                  35           c           173                                                  36           a           135                                                               b           157                                                  37           a           146                                                  38           b           203                                                  39           b           165                                                               c           214                                                  40           f           205                                                  41           c           157                                                  42           f           187                                                  43           b           226                                                  44           c           164                                                               f           217                                                  45           b           164                                                               c           220                                                  46           c           157                                                               f           210                                                  47           c           150                                                               f           210                                                  48           f           172                                                  49           f           207                                                  50           e           155                                                  51           c           136                                                               f           207                                                  52           c           162                                                               f           203                                                  53           c           165                                                               f           239                                                  54           c           144                                                               f           208                                                  55           c           162                                                  56           c           165                                                               f           219                                                  57           c           162                                                               f           208                                                  58           c           162                                                               f           216                                                  59           c           146                                                               f           218                                                  60           b           176                                                               c           210                                                  61           b           176                                                               c           220                                                  62           b           155                                                               c           210                                                  63           d           150                                                               g           205                                                  64           c           165                                                               f           210                                                  65           f           175                                                  66           f           171                                                  67           f           188                                                  68           c           148                                                               f           210                                                  69           b           179                                                               c           222                                                  70           b           135                                                               c           181                                                  71           b           157                                                  72           b           167                                                  73           b           176                                                               c           229                                                  74           b           186                                                  75           b           153                                                               c           197                                                  76           b           135                                                               c           184                                                  77           b           135                                                               c           186                                                  78           c           146                                                               f           176                                                  79           c           179                                                  80           c           139                                                               f           184                                                  81           b           139                                                               c           173                                                  82           c           148                                                               f           205                                                  83           c           144                                                               f           208                                                  84           c           145                                                               f           208                                                  85           f           157                                                  86           f           136                                                  87           c           134                                                               f           183                                                  88           d           157                                                  89           f           173                                                  90           b           162                                                  91           c           173                                                  92           b           146                                                               c           192                                                  93           f           165                                                  94           f           183                                                  95           c           173                                                  96           c           162                                                  97           b           156                                                  98           f           187                                                  99           f           136                                                  100          f           157                                                  101          c           171                                                               f           225                                                  102          f           187                                                  103          c           146                                                               f           203                                                  104          c           137                                                  105          f           216                                                  106          b           173                                                  107          c           139                                                               f           185                                                  108          d           163                                                  109          e           145                                                  110          c           154                                                  111          e           175                                                  112          d           148                                                  113          c           138                                                  114          c           130                                                  115          b           135                                                  116          c           130                                                  117          c           135                                                  118          c           135                                                  119          c           153                                                  120          c           148                                                  121          c           146                                                  122          c           135                                                  123          c           135                                                  124          f           151                                                  125          d           140                                                  126          f           150                                                  127          b           130                                                  128          d           146                                                  129          i           167                                                  130          i           141                                                  131          f           148                                                  132          c           136                                                               f           146                                                  133          f           139                                                  134          a           192                                                               b           175                                                  135          b           167                                                  147          b           214                                                  148          b           185                                                               c           250                                                  149          b           203                                                  150          b           200                                                               c           205                                                  151          b           155                                                               c           224                                                  152          b           157                                                               c           210                                                  153          b           203                                                               c           243                                                  154          b           205                                                               c           214                                                  155          b           171                                                               c           183                                                  156          c           160                                                               f           218                                                  157          c           153                                                               f           201                                                  158          c           174                                                               f           205                                                  159          c           171                                                               f           216                                                  160          c           160                                                               f           218                                                  161          c           169                                                               f           234                                                  162          c           157                                                               f           243                                                  163          c           156                                                               f           227                                                  164          b           198                                                  165          b           189                                                  166          a           138                                                  167          b           198                                                  168          b           167                                                  169          b           202                                                  170          b           198                                                  171          c           186                                                               f           212                                                  172          c           148                                                               f           195                                                  173          c           152                                                               f           192                                                  174          c           148                                                               f           198                                                  175          c           145                                                               f           208                                                  176          c           155                                                               f           208                                                  177          c           153                                                               f           208                                                  178          c           142                                                               f           181                                                  179          c           136                                                               f           208                                                  180          c           145                                                               f           208                                                  181          c           145                                                               f           208                                                  182          c           153                                                               f           192                                                  183          c           153                                                               f           192                                                  184          c           162                                                               f           199                                                  185          c           142                                                               f           192                                                  186          c           176                                                  187          c           130                                                               f           216                                                  188          c           193                                                  189          c           146                                                               f           214                                                  190          c           145                                                               f           208                                                  191          b           155                                                  192          a           153                                                               b           199                                                  193          a           162                                                  194          b           130                                                               c           192                                                  195          c           165                                                  196          c           208                                                  197          c           144                                                               f           171                                                  198          c           176                                                  199          d           159                                                  200          c           168                                                  201          c           162                                                  202          c           174                                                  203          e           180                                                  204          c           174                                                  205          c           153                                                               f           173                                                  206          c           139                                                               f           180                                                  207          c           130                                                               f           192                                                  208          c           136                                                               f           192                                                  209          c           134                                                               f           192                                                  210          c           186                                                  211          f           176                                                  212          f           153                                                  213          f           160                                                  214          c           130                                                               f           198                                                  215          c           131                                                               f           158                                                  216          c           171                                                  217          f           181                                                  218          f           176                                                  219          c           130                                                               f           182                                                  220          d           157                                                  221          f           168                                                  222          c           144                                                               f           162                                                  223          e           172                                                  224          d           148                                                  225          e           148                                                  226          c           145                                                  227          f           143                                                  228          e           140                                                  229          e           167                                                  230          f           144                                                  231          b           150                                                  232          a           146                                                  233          e           165                                                  234          c           135                                                  235          c           145                                                  236          c           145                                                  237          e           242                                                  238          c           130                                                               f           192                                                  239          e           153                                                  240          e           158                                                  241          f           135                                                  242          b           137                                                  ______________________________________                                         Note:                                                                         .sup.(1) Symbols a to i denote the following doses:                           a: 10 mg/kg × 3                                                         b: 20 mg/kg × 3                                                         c: 40 mg/kg × 3                                                         d: 50 mg/kg × 3                                                         e: 60 mg/kg × 3                                                         f: 80 mg/kg × 3                                                         g: 100 mg/kg × 3                                                        h: 120 mg/kg × 3                                                        i: 160 mg/kg × 3                                                        .sup.(2) Ratio of medium survival time of test and control animals.      

For comparison, the same treatment as described above was carried outusing, at a dose of 50 mg/kg/day x 3, a chartreusin suspension preparedby the preparation method described in "Cancer Research, Vol. 37, p.1666-1672 (1977)" [a method comprising dissolving chartruesin in a mixedsolution of 0.2M Na₂ HPO₄ and N,N-dimethylacetamide (4:1 by volume) at aconcentration of 5 mg/ml]. In this case, T/C (%) was calculated as 105%.

(2) Acute Toxicity

In Table 7 are shown acute toxicity values (LD₅₀, mg/kg) in ddY mice inthe case of intravenously administering (once) each of the compounds ofthis invention in the form of preparations shown in the PreparationExamples shown in Table 7.

                  TABLE 7                                                         ______________________________________                                                          Preparation                                                                   Example   LD.sub.50                                         Compound No.      No.       (mg/kg)                                           ______________________________________                                        166               1          30 or more                                       27, 37, 90, 97, 116, 117,                                                                       3                                                           14                7                                                           15                11                                                          34, 134           18                                                          147               1          40 or more                                       19, 26, 72, 74, 113, 115,                                                                       2                                                           123, 135                                                                      12, 13, 20-25, 38, 39, 43,                                                                      3                                                           55, 60-62, 69-71, 73, 75-77,                                                  79, 81, 91, 92, 95, 96, 106,                                                  114, 118, 119, 121, 122, 127,                                                 148-155, 159, 164, 167-170,                                                   192-195, 216, 234, 242.                                                       120               5                                                           35                7                                                           32, 36            10                                                          2-4, 16           12                                                          33                13                                                          6, 18             14                                                          191, 231, 232     15                                                          1, 8-11, 17       19                                                          199, 220, 224     4          60 or more                                       67, 110, 202, 210 5                                                           65, 66, 188, 201, 203, 204,                                                                     6                                                           223, 225, 228, 233, 235, 237,                                                 239, 240                                                                      29, 30, 31, 44-46, 52-54,                                                                       5          80 or more                                       56, 58, 68, 83, 84, 89, 93,                                                   94, 101, 156, 157, 160-163,                                                   174, 176, 180, 184, 197, 221                                                  47, 57, 64, 82, 103-105, 124,                                                                   6                                                           158, 171-173, 175, 177-179,                                                   181-183, 185-187, 189, 190,                                                   196, 198, 200, 205, 206,                                                      207-209, 211, 214, 217-219,                                                   222, 229, 236, 238, 241                                                       212, 213, 215, 227, 230                                                                         16                                                          80                19                                                          112               2         100 or more                                       88, 109, 111, 125, 126, 128                                                                     4                                                           40, 50, 51, 85, 87, 107,                                                                        5                                                           132, 133                                                                      86, 102, 131      6                                                           108               8                                                           41, 78, 98, 99    17                                                          59                19                                                          42                20                                                          28                5         120 or more                                       63                8                                                           48                9                                                           49                5         150 or more                                       129               6         180 or more                                       100, 130          17                                                          ______________________________________                                    

(3) Doses and Administration Routes

As to administration routes in the case of animals, the compounds ofthis invention are administered as injections such as intraperitonealinjection, intravenous injection, local injection and the like, or asoral drugs. In the case of human beings, said compounds are administeredas injections such as intravascular (intravenous or intraarterial)injection, local injection and the like, or as oral drugs, suppositoriesor the like. As to the dose, said compounds are administeredcontinuously or intermittently in a range in which the total dose doesnot exceed a certain level, in consideration of the results of animalexperiments and various conditions. However, the dose may, of course, beproperly varied depending on the administration route, and on theconditions of a patient or an animal to be treated (for example, age,body weight, sex, sensitivity, food and the like), interval ofadministration, drugs used in combination with said compounds and thedegree of disease. An optimum dose and the number of administrationsunder certain conditions should be determined by medical specialists.The autitumorous composition of this invention are prepared in the samemanner as for conventional drugs. For example, they are prepared from anactive ingredient and various pharmacologically acceptable adjuvantssuch as inactive diluent and the like. Intravenous administration.ofthese antitumorous composition is most suitable. The content of activeingredient in the antitumorous compositions of this invention may varydepending on various conditions and cannot be determined uniquely. It issufficient that the active ingredient is contained similarly to the caseof conventional antitumorous compositions. For example, the activeingredient may be contained in an amount of at least 0.001%.

Next, preparation Examples of the antitumorous compositions of thisinvention are described below.

PREPARATION EXAMPLE 1

With 2.0 mg of yellow powder of the exo form of6-O-(N-trifluoroacetyl-β-amino-isobutyryl)-3',4'-O-(m-fluorobenzylidene)-chartreusin(compound No. 37) was sufficiently mixed 0.16 ml of Tween-80, afterwhich 2.0 ml of physiological saline was added in small portions toprepare a solution.

PREPARATION EXAMPLE 2

With 5.2 mg of yellow powder of the exo form of6-O-(N-trifluoroacetyl-2-amino-cyclohexanecarbonyl)-3',4'-O-benzylidene-chartreusin(compound No. 26) was sufficiently mixed 0.20 ml of Tween-80, afterwhich 2.5 ml of physiological saline was added in small portions toprepare a solution.

PREPARATION EXAMPLE 3

With 5.2 mg of yellow powder of the exo-form of6-O-(N-trifluoroacetyl-β-amino-isobutyryl)-3',4'-O-benzylidene-chartreusin(compound No. 12) was sufficiently mixed 0.20 ml of Tween-80, afterwhich 2.5 ml of physiological saline was added in small portions toprepare a suspension.

PREPARATION EXAMPLE 4

With 6.5 mg of yellow powder of6-O-(3-benzoylpropionyl)-3',4'-O-isopropylidene-chartreusin (compoundNo. 224) was sufficiently mixed 0.20 ml of Tween-80, after which 2.5 mlof physiological saline was added in small portions to prepare asuspension.

PREPARATION EXAMPLE 5

With 10.4 mg of yellow powder of the endo-form of6-O-(N-trifluoroacetyl-β-alanyl)-3',4'-O-benzylidene-chartreusin(compound No. 131) was sufficiently mixed 0.20 ml of Tween-80, afterwhich 2.5 ml of physiological saline was added in small portions toprepare a solution.

PREPARATION EXAMPLE 6

In the same manner as in Preparation Example 5, the endo form of6-O-(N-benzoyl-β-alanyl)-3',4'-O-(m-fluorobenzylidene)-chartreusin(compound No. 47) was formed into a suspension.

PREPARATION EXAMPLE 7

With 7.6 mg of yellow powder of the exo form of6-O-(α-isopropyl-β-alanyl)-3',4'-O-benzylidene-chartreusin phosphate(compound No. 35) was sufficiently mixed 0.19 ml of Tween-80, afterwhich 3.8 ml of physiological saline was added in small portions toprepare a solution.

PREPARATION EXAMPLE 8

With 10 mg of yellow powder of6-O-(N-carbobenzyloxyglycyl)-3',4'-O-isopropylidene-chartreusin(compound No. 108) was sufficiently mixed 0.1 ml of Tween-80, afterwhich 1.9 ml of physiological saline was added in small portions toprepare a suspension.

PREPARATION EXAMPLE 9

With 20 mg of yellow powder of6-O-(N-formyl-β-alanyl)-3',4'-O-isopropylidene-chartreusin (compound No.48) was sufficiently mixed 0.2 ml of Tween-80, after which 1.8 ml ofphysiological saline was added in small portions to prepare a solution.

PREPARATION EXAMPLE 10

With 3.2 mg of yellow powder of the exo form of6-O-(glycyl-glycyl-valyl)-3',4'-O-benzylidene-chartreusin phosphate(compound No. 36) was sufficiently mixed 0.04 ml of Tween-80, afterwhich 1.6 ml of physiological saline was added in small portions toprepare a solution.

PREPARATION EXAMPLE 11

With 3.2 mg of yellow powder of the exo form of6-O-(N,N-diethyl-β-alanyl)-3',4'-O-(m-fluorobenzylidene)-chartreusinhydrochloride (compound No. 15) was sufficiently mixed 0.03 ml ofTween-80, after which 1.6 ml of physiological saline was added in smallportions to prepare a solution.

PREPARATION EXAMPLE 12

To 7.6 mg of yellow powder of the exo form of6-O-(β-alanyl)-3',4'-O-(m-fluorobenzylidene)-chartreusin phosphate(compound No. 16) were added 0.06 ml of Tween-80 and 3.8 ml ofphysiological saline to form a solution.

PREPARATION EXAMPLE 13

With 7.6 mg of yellow powder of the exo form of6-O-(glycyl-β-alanyl)-3',4'-O-(m-fluorobenzylidene)-chartreusinphosphate (compound No. 33) was sufficiently mixed 0.11 ml of Tween-80,after which 1.9 ml of physiological saline was added in small portionsto prepare a solution.

PREPARATION EXAMPLE 14

With 13.8 mg of yellow powder of the exo form of6-O-(β-amino-isobutyryl)-3',4'-O-benzylidene-chartreusin phosphate(compound No. 6) was sufficiently mixed 0.07 ml of Tween-80, after which2.3 ml of physiological saline was added in small portions to prepare asolution.

PREPARATION EXAMPLE 15

With 6.4 mg of yellow powder of the exo form of6-O-(n-butyryl)-3',4'-O-benzylidene-chartreusin (compound No. 191) wassufficiently mixed 16 mg of sodium carboxymethyl cellulose, after which3.2 ml of physiological saline was added in small portions to obtain asuspension.

PREPARATION EXAMPLE 16

With 12.8 mg of yellow powder of the endo form of6-O-(n-butyryl)-3',4'-O-benzylidene-chartreusin (compound No. 212) wassufficiently mixed 16 mg of sodium carboxymethyl cellulose, after which3.2 ml of physiological saline was added in small portions to prepare asuspension.

PREPARATION EXAMPLE 17

With 16 mg of yellow powder of6-O-(N-trifluoroacetyl-6-amino-n-hexanoyl)-3',4'-O-benzylidene-chartreusin(compound No. 78) was sufficiently mixed 10 mg of sodium carboxymethylcellulose, after which 2 ml of physiological saline wa added in smallportions to prepare a suspension.

PREPARATION EXAMPLE 18

To 3.2 mg of yellow powder of the exo form of6-O-(β-1-pyrrolidinyl-propionyl)-3',4'-O-(m-fluorobenzylidene)-chartreusinphosphate (compound No. 34) was added 1.6 ml of physiological saline toform a solution.

PREPARATION EXAMPLE 19

To 10.4 mg of yellow powder of the endo form of6-O-(β-alanyl)-3',4'-O-benzylidene-chartreusin hydrochloride (compoundNo. 80) was added 2.6 ml of physiological saline to form a solution.

PREPARATION EXAMPLE 20

To 16 mg of 6-O-(β-alanyl)-3',4'-O-isopropylidene-chartreusinhydrochloride (compound No. 42) was added 2 ml of physiological salineto form a solution.

PREPARATION EXAMPLE 21

In 0.07 ml of dimethylformamide was dissolved 18 mg of yellow powder ofthe exo form of 6-O-(N-trifluoroacetyl-β-amino-isobutyryl)-3',4'-O-benzylidene-chartreusin (compound No. 12),followed by adding thereto 0.11 ml of Tween-80 and 0.33 ml of a mixtureof HCO-60 and propylene glycol (2:1). After they were sufficientlymixed, 2.50 ml of physiological saline was added thereto to prepare asolution.

PREPARATION EXAMPLE 22

With 9.6 mg of yellow powder of 6-O-(N-trifluoroacetyl-β-alanyl)-3',4'-O-isopropylidene-chartreusin (compound No. 49) wassufficiently mixed 12 mg of mannitol, after which 1.2 ml ofphysiological saline was added in small portions to prepare asuspension.

What is claimed is:
 1. A chartreusin derivative fo the formula (I) or asalt thereof: ##STR172## wherein X₁ is a hydrogen atom or a C₁₋₃ alkylgroup which may be substituted by a halogen atom, a C₁₋₂ alkoxy group,or a C₁₋₂ alkylthio group;X₂ is a C₁₋₃ alkyl group which may besubstituted by a halogen atom or a C₁₋₂ alkoxy group or a C₁₋₂ alkylthiogroup,a C₁₋₂ alkylcarbonyl-C₁₋₂ alkyl group which may be substituted bya halogen atom, a pheynyl group, a phenyl-C₁₋₂ alkyl group, a furylgroup, or a thienyl groupwherein each of the phenyl group, thephenyl-C₁₋₂ alkyl group, the furyl group and the thienyl group may besubsituted by a halogen atom, a cyano group, a nitro group, a C₁₋₃ alkylgroup, a C₁₋₃ alkoxy group, a C₁₋₃ alkylthio group, a C₁₋₃ alkycarbonylgroup, a C₁₋₃ alkoxycarbonyl group or a di-C₁₋₃ alkylamino group whereineach of the C₁₋₃ alkyl group, the C₁₋₃ alkoxy group, the C₁₋₃ alkylthiogroup, the C₁₋₃ alkylcarbonyl group, the C₁₋₃ alkoxycarbonyl group andthe di-C₁₋₃ alkylamino group may be substituted by a halogen atom; inthe case where both X₁ and X₂ are said alkyl groups, the total number ofcarbon atoms of these alkyl groups is 4 or less; X₁ is a hdyrogen atomin the case where X₂ is said phenyl group, said phenyl-C₁₋₂ alkyl group,said furyl group, or said thienyl group; X₁ and X₂, when taken togetherwith the adjacent carbon atom, may form a C₃₋₇ cycloalkylidene which maybe substituted by a halogen atom, a C₁₋₂ alkoxy group or a C₁₋₂alkylthio group; and Q is ##STR173## wherein each of R, R' and R" is aC₁₋₁₁ alkanediyl group,a C₂₋₁₁ alkenediyl group, a C₂₋₁₁ alkynediylgroup, a C₃₋₁₀ cycloalkanediyl group, a C₅₋₁₀ cycloalkenediyl groupwherein each of the C₁₋₁₁ alkanediyl group, the C₂₋₁₁ alkenediyl group,the C₂₋₁₁ alkynediyl group, the C₃₋₁₀ cycloalkanediyl group and theC₅₋₁₀ cycloalkenediyl group may be substituted by a halogen atom, ahydroxyl group, a mercapto group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthiogroup, a C₁₋₆ alkylsulfinyl group, a C₁₋₆ alkylsulfonyl group, anaminocarbonyl group, a hydroxycarbonyl group, a C₁₋₅ alkoxycarbonylgroup, a phenyl group which may be sbustituted by a halogen atom or ahydroxyl group or a mercapto group or a C₁₋₃ alkoxy group or a C₁₋₃alkylthio group, or a 3-indolyl group which may be substittued by ahalogen atom, or each of R, R' and R" is a phenylene group which may besubstituted by a halogen atom, a hydroxyl group, a mercapto group, aC₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylsulfinyl group, aC₁₋₆ alkylsulfonyl group, an aminocarbonyl group, a hydroxycarbonylgroup, or a C₁₋₅ alkoxycarbonyl group;, atom, or each of Z₁, Z'₁ and Z"₁is a hydrogen atom, on a C₁₋₆ alkyl group which may be substituted by ahalogen atom, a hydroxyl group, a mercapto group, a C₁₋₃ alkoxy group,or a C₁₋₃ alkylthio group; Z₂ is a hydrogen atom,a formyl group, a C₁₋₆alkyl group, a C₁₋₆ alkylcarbonyl group, a benzoyl groupwherein each ofthe C₁₋₆ alkyl group, the C₁₋₆ alkylcarbonyl group and the benzoyl groupmay be substituted by the same substituent as substituent for said C₁₋₆alkyl group as each of Z₁, Z'₁ and Z"_(l), or Z₂ is a benzyloxycarbonylgroup which may be substituted by a halogen atom; Z₁ and Z₂, when takentogether with the nitrogen atom, may form a nitrogen-containing C₂₋₁₀heterocyclic group which may be substituted by the same substituent assubstituent for said C₁₋₆ alkyl group as each of Z₁, Z'₁ and Z"₁, or Qisa C₁₋₁₁ alkyl group, a C₂₋₁₁ alkenyl group, a C₃₋₁₁ alkynyl group, aC₃₋₁₀ cycloalkyl group, a C₅₋₁₀ cycloalkenyl group, a C₁₋₁₀alkylcarbonyl group, a C₁₋₁₀ alkoxycarbonyl groupwherein each of theC₁₋₁₁ alkyl group, the C₂₋₁₁ alkenyl group, the C₃₋₁₁ alkynyl group, theC₃₋₁₀ cycloalkyl group, the C₅₋₁₀ cycloalkenyl group, the C₁₋₁₀alkylcarbonyl group and the C₁₋₁₀ alkoxycarbonyl group may besubstituted by a halogen atom a hydroxyl group, a mercapto group, acyano group, a nitro group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group,a C₁₋₆ alkylsulfinyl group, a C₁₋₆ alkylsulfonyl group, a C₁₋₆alkylcarbonyl group, a C₁₋₆ alkoxycarbonyl group, a phenoxycarbonylgroup, a C₁₋₆ alkylcarbonyloxy group, a C₃₋₇ cycloakyl group, a phenylgroup, a phenoxy group, a phenylthio group, a phenylsulfinyl group, aphenylsulfonyl group, a benzoyl group, a benzolyoxy group or a benzyloxygroup wherein each of the C₁₋₆ alkoxy group, the C₁₋₆ alkylthio group,the C₁₋₆ alkylsulfinyl group, the C₁₋₆ alkylsulfonyl group, the C₁₋₆alkylcarbonyl group, the C₁₋₆ alkoxycarbonyl group, the phenoxycarbonylgroup, the C₁₋₆ alkylcarbonyloxy group, the C₃₋₇ cycloalkyl group, thephenyl group, the phenyoxy group, the phenylthio group, thephenylsulfinyl group, the phenylsulfonyl group, the benzoyl group, thebenzoyloxy group, and benzyloxy group may be substituted by the samesubstituent as substituted for said C₁₋₆ alkyl group as each of Z₁, Z'₁,and Z₁ ", or Q is a phenyl group which may be substituted by a halogenatom, a hydroxyl group, a mercapto group, a cyano group, a nitro group,a C₁₋₆ alkylsulfinyl group, a C₁₋₆ alkylsulfonyl group, a C₁₋₆ alkylgroup, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylcarbonylgroup, a C₁₋₆ alkoxycarbonyl group, or a C₁₋₆ alkylcarbonyloxygroupwherein each of the C₁₋₆ alkyl group, the C₁₋₆ alkoxy group, theC₁₋₆ alkylthio group, the C₁₋₆ alkylcarbonyl group, the C₁₋₆alkoxycaronyl group, and the C₁₋₆ alkylcarbonyloxy group may besubstituted by the same substituent as substituent for said C₁₋₆ alkylgroup as each of Z₁, Z'₁ and Z₁ ", the total number of atoms of Q otherthan hydrogen atom being 30 or less.
 2. A chartreusin derivative or asalt thereof according to claim 1 wherein Q is ##STR174##
 3. Achartreusin derivative or a salt thereof according to claim 1 wherein X₁is a hydrogen atom; X₂ is said phenyl group, said furyl group, or saidthienyl group; each of R, R' and R" is said C₁₋₁₁ alkanediyl group orsaid C3-10 cycloalkanediyl group; and the total number of atoms of Qother than hydrogen atom is 20 or less.
 4. A chartreusin derivative or asalt thereof according to claim 3, wherein X₂ is said phenyl group.
 5. Achartreusin derivative or a salt thereof according to calim 4 wherein X₂is said phenyl group which may be substituted in the o-position, them-position or the o-, m-positions of the benzene nucleus; and the totalnumber of atoms of Q other than hydrogen atom is 15 or less.
 6. Achartreusin derivative or a salt thereof acording to claim 5, which isin exo form.
 7. A chartreusin derivative or salt thereof according toclaim 6, wherein X₂ is a phenyl group which may be substituted by afluorine atom in the m-position of the benzene nucleus.
 8. A chartreusinderivative or salt thereof according to claim 78 wherein X₂ is a phenylgroup.
 9. A chartreusin derivative according to claim 1, wherein Q issaid C₁₋₁₁ alkyl group, said C₂₋₁₁ alkenyl group, said C₃₋₁₁ alknylgroup, said C₃₋₁₀ cycloalkyl group, said C₅₋₁₀ cycloalkenyl group, saidC₁₋₁₀ alkylcarbonyl group, said C₁₋₁₀ alkoxycarbonylgroup or said phenylgroup.
 10. A chartreusin derivative according to claim 1, wherein X₁ isa hydrogne atom; X₂ is said phenyl group, said furyl group, or saidthienyl group; and Q is said C₁₋₁₁ alkyl group, said C₂₋₁₁ alkenylgroup, said C₃₋₁₀ cycloalkyl group or said phenyl group, the totalnumber of atoms of Q other than hydrogen atom being 20 or less.
 11. Achartreusin derivative according to claim 10, wherein X₂ is said phenylgroup; Q is said C₁₋₁₁ alkyl group or said C₃₋₁₀ cycloalkyl group.
 12. Achartreusin derivative according to claim 11, wherein X₂ is said phenylgroup which may be substituted in the o-position, m-position, or o-,m-positions of the benzene nucleus; and the total number of atoms of Qother than hydrogen atom is 15 or less.
 13. A chartreusin derivativeaccording to claim 12, which is in the exo form.
 14. A chartreusinderivative according to claim 13 wherein X₂ is a phenyl group which maybe substituted by a flourine atom in the m-position for the benzenenucleus.
 15. A chartreusin derivative according to claim 14, wherein X₂is phenyl group.
 16. A chartreusin derivative or a salt thereof ccordingto claim 2, wherein the derivative is the exo form of6-O-(N,N-dimethyl-β-amino-isobutyryl)-3', 4'-O-benzylidene-chartreusin.17. A chartreusin derivative or a salt thereof according to claim 2,wherein the derivative is the exo form of6-O-(N-isopropyl-β-amino-isobutyryl)-3', 4'-O-benzylindene-chartreusin.18. A chartreusin derivative or a salt thereof according to claim 2,wherein the derivative is the exo form of6-O-(N-glycyl-β-amino-isobutyryl)-3',4'-O-benzylidene-chartreusin.
 19. Achartreusin derivative or a salt thereof according,to claim 2, whereinthe derivative is the exo form of6-O-[N-(N',N'-dimethyl-glycyl)-]-amino-isobutyryl]-3',4'-O-benzylidene-chartreusin.20. A chartreusin derivative or a salt thereof6-O-(β-amino-isobutyryl)-3',''-O- enzylidene-chartreusin. according toclaim 2, wherein the derivative is the exo form of6-O-(β-amino-isobutryl)3',4'-O-benzylidene-chartreusin.
 21. Achartreusinderivative or a salt thereof according to claim 2, wherein thederivative is the exo form of 6-O-(N,N-diethyl-β-alanyl)-3',4'-O-benzylidene-chartreusin.
 22. A chartreusin derivative or a saltthereof according to claim 2, wherein the derivative is the exo form of6-O-(β-1-pyrrolidinyl-propionyl)-3',4'-O-benzylidene-chartreusin.
 23. Achartreusin derivative or a salt thereof according to claim 2, whereinthe derivative is the exo form of6-O-(N-glycyl-β-alanyl)-3',4'-O-benzylidene-chartreusin.
 24. Achartreusin derivative according to claim 2, wherein the derivative isthe exo form of6-O-(N-trifluoroacetyl-β-amino-isobutyrl)-3',4'-O-benzylidene-chartreusin.25. A chartreusin derivative according to claim 2, wherein thederivative is the exo form of6-O-(N-benzoyl-β-aminoisobutyryl)-3',4'-O-benzylidene-chartreusin.
 26. Achartreusin derivative or a salt thereof according to claim 2, whereinthe derivative is the exo form of6-O-(β-amino-isobutyryl)-3',4',-O-(m-fluorobenzylidene)-chartreusin. 27.A chartreusin derivative or a salt thereof according to claim 2, whereinthe derivative is the exo form of6-O-(β-alanyl)-3',4'-O-benzylidene-chartreusin.
 28. A chartreusinderivative or a salt thereof according to claim 2, wherein thederivative is the exo form of6-O-(β-morpholino-propionyl)-3',4'-O-benzylidene-chartreusin.
 29. Achartreusin derivative or a salt thereof according to claim 2, whereinthe derivative is the exo form of6-O-(N,N-dimethyl-α-ethyl-propionyl)-3',4'-O-benzylindene-chartreusin.30. A chartreusin derivative or a salt thereof according to claim 2,wherein the derivative is the exo form of6-O-(N,N-dimetyl-β-alanyl)-3',4'-O-benzylidene-chartreusin.
 31. Achartreusin derivative or a salt thereof according to claim 2, whereinthe derivative is the exo form of6-O-(N-methyl-β-amino-isobutyryl)-3',4'-O-benzylidene-chartreusin.
 32. Achartreusin derivative or a salt thereof according to claim 2, whereinthe derivative is the exo form of6-O-(N-methyl-β-alanyl)-3',4'-O-benzylidene-chartreusin.
 33. Achartreusin derivative according to claim 9, wherein the, derivative isthe exo form of6-O-(4-hydroxy-n-butyryl)-3',4'-O-benzylidene-chartreusin.
 34. Achartreusin derivative according to claim 9, wherein the derivative isthe exo form of 6-O-(2-acetoxyacetyl)-3', 4'-O-benzylidene-chartreusin.35. A chartreusin derivative according to claim 9, wherein thederivative is the exo form of6-O-[2-(3-chloropropionyloxy)-acetyl]-3',4'-O-benzylidene-chartreusin.36. A chartreusin derivative according to claim 9, wherein thederivative is the exo form of6-O-(3-methanesulfinyl-propionyl)-3',4'-O-benzylidene-chartreusin.
 37. Achartreusin derivative according to claim 9, wherein the derivative isthe exo form of 6-O-(3-methyl-carbonylpropionyl)-3',4'-O-benzylidene-chartreusin.
 38. A chartreusin derivative according toclaim 9, wherein the derivative is the exo form of6-O-(3-phenylpropionyl)-3', 4'-O-benzylidene-chartreusin.
 39. Achartreusin derivative according to claim 9, wherein the derivative isthe exo form of6-O-(3-methyl-n-butyryl)-3',4'-O-benzylidene-chartreusin.
 40. Achartreusin derivative, as an intermediate, of the formula: ##STR175##wherein X₁ is a hydrogen atom or a C₁₋₃ alkyl group which may besubstituted by a halogen atom, a C₁₋₂ alkoxy group, or a C₁₋₂ alkylthiogroup;X₂ isa C₁₋₃ alkyl group which may be substituted by a halogen atomor a C₁₋₂ alkoxy group or a C₁₋₂ alkylthio group, a C₁₋₂alkylcarbonyl-C₁₋₂ alkyl group which may be substituted by a halogenatom, a phenyl group, a phenyl-C₁₋₂ alkyl group, a furyl group or athienyl groupwherein each of the phenyl group, the phenyl-C₁₋₂ alkylgroup, the fury group and the thienyl group may be substituted by ahalogen atom, a cyano group, a nitro group, a C₁₋₃ alkyl group, a C₁₋₃alkoxy group, a C₁₋₃ alkylthio group, a C₁₋₃ alkycarbonyl group, a C₁₋₃alkoxycarbonyl group or a di-C₁₋₃ alkylamino group wherein each of theC₁₋₃ alkyl group, the C₁₋₃ alkoxy group, the C₁₋₃ akylthio group, theC₁₋₃ alkylcarbonyl group, the C₁₋₃ alkoxycarbonyl group and the di-C₁₋₃akylamino group may be substituted by a halogen atom; in the case where,both X₁ and X₂ are said alkyl groups, the total number of carbon atomsof these alkyl groups is 4 or less; X₁ is a hydrogen atom in the casewhere X₂ is said phenyl group, said phenyl-C₁₋₂ alkyl group, said furylgroup, or said thienyl group; X₁ and X₂, when taken together with theadjacent carbon atom, may form a C₃₋₇ cycloalkylidene which may besubstituted by a halogen atom, a C₁₋₂ alkoxy group or a C₁₋₂ alkylthiogroup; each of T₁ and T₂ is a hydrogen atom or a silyl group substitutedby a text-butyl dimetyl group, T₁ being said silyl group in the casewhere T₂ is said silyl group.
 41. A chartreusin derivative as anintermediate according to claim 40, wherein both T₁ and T₂ are hydrogenatoms.
 42. A chartreusin derivative as an intermediate according toclaim 40 wherein X₁ is a hydrogen atom; X₂ is said phenyl group, saidfuryl group, or said thienyl group.
 43. A chartreusin derivative as anintermediate according to claim 42, wherein X₂ is said phenyl group. 44.A chartreusin derivative as an intermediate according to claim 43, whichis in the exo form and wherein X₂ is said phenyl group which may besubstituted in the o-position, m-position or o-,m-positions of thebenzene nucleus.
 45. A chartreusin derivative as an intermediateaccording to claim 44 wherein X₂ is said phenyl group which may besubstituted in the m-position of the benzene nucleus.
 46. A chartreusinderivatie as an intermediate according to claim 45 wherein X₂ is aphenyl group.
 47. A chartreusin derivative as an intermediate accordingto claim 40, wherein T₁ is tert-bytyldimethysilyl group, and T₂ is ahydrogen atom.
 48. A chartreusin derivative as an intermediate accordingto claim 40, wherein both T₁ and T₂ are tertbutyldimethyl groups.
 49. A6-O-substituted chartreusin derivative of the formula (XII): ##STR176##wherein Q is ##STR177## wherein each of R and R' and R" is a C₁₋₁₁alkanediyl group,a C₂₋₁₁ alkenediyl group, a C₂₋₁₁ alkynediyl group, aC₃₋₁₀ cycloalkanediyl group, a C₅₋₁₀ cycloalkenediyl groupwherein eachof the C₁₋₁₁ alkanediyl group, the C₂₋₁₁ akenediyl group, the C₂₋₁₁alkynediyl group, the C₃₋₁₀ cycloalkanediyl group and the C₅₋₁₀cycloalkenediyl group may be substituted by a halogen atom, a hydroxylgroup, a mercapto group, a C₁₋₆ alkoxy group, a C₁₋₆ alkythio group, aC₁₋₆ alkylsulfinyl group, a C₁₋₆ alkylsulfonyl group, an aminocarbonylgroup, a hydroxycarbonyl group, a C₁₋₅ alkoxycarbonyl group, a phenylgroup which may be substituted by a halogen atom or a hydroxy group or amercapto group or a C₁₋₃ alkoxy group or a C₁₋₃ alkylthio group, or a3-indolyl group which may be substituted by a halogen atom, or each orR, R' and R" is a phenyllene group which may be substituted by a halogenatom, a hydroxyl group, a mercapto group, a C₁₋₆ akoxy group, a C₁₋₆alkylthio group, a C₁₋₆ alkylsufinyl group, or a C₁₋₅ akoxycarbonylgroup; each of Z₁, Z'₁ and Z"₁ is a hydrogen atom, or a C₁₋₆ alkyl groupwhich may be substituted by a halogen atom, a hydroxyl group, a mercaptogroup, a C₁₋₃ alkoxy group, or a C₁₋₃ alkylthio group; Z₂ isa hydrogenatom, a formyl group, a C₁₋₆ alkyl group, a C₁₋₆ alkylcarbonyl group, abenzoyl groupwherein each of the C₁₋₆ alkyl group, the C₁₋₆alkylcarbonyl group and the benzoyl group may be substituted by the samesubstitutent as substitutent for said C₁₋₆ alkyl group as each of Z₁,Z'₁ and Z"₁, or Z₂ is a benzyloxycarbonyl group which may be substitutedby a halogen atom; Z₁ and Z₂, when taken togehter with the nitrogenatom, may form a nitrogen-containing C₂₋₁₀ heterocyclic group which maybe substituted by the same substituent as substitutent for said C₁₋₆alkyl group as each of Z₁, Z'₁ and Z"₁, or Q isa C₁₋₁₁ alkyl group, aC₂₋₁₁ alkenyl group, a C₃₋₁₁ alkynyl group, a C₃₋₁₀ cycloalkyl group, aC₅₋₁₀ cycloalkenyl group, a C₁₋₁₀ alkylcarbonyl group, a C₁₋₁₀akoxycarbonyl group,wherein each of the C₁₋₁₁ alkyl group, the C₂-alkenyl group, the C₃₋₁₁ alkynyl group, the C₃₋₁₀ cycloalkyl group, theC₅₋₁₀ cycloalkenyl group, the C₁₋₁₀ alkylcarbonyl group and the C₁₋₁₀alkxoycarbonyl group may be substituted by a halogen atom, a hydroxylgroup, a mercapto group, a cyano group, a notro group, a C₁₋₆ alkoxygroup, a C₁₋₆ akylthio group, a C₁₋₆ alkylsulfinyl group, a C₁₋₆alkylsulfonyl group, a C₁₋₆ alkylcarbonyl group, a C₁₋₆ alkoxycarbonylgroup, a C₁₋₆ phenyoxycarbonyl group, a C₁₋₆ alkylcarbonyloxy group, aC₃₋₇ cycloalkyl group, a phenyl group, a phenoxy group, a phenylthiogroup, a phenylsulfinyl group, a phenylsulfonyl group, a benzoyl group,a benzoyloxy group or a benzyloxy group wherein each of the C₁₋₆ alkoxygroup, the C₁₋₆ alkylthio group, the C₁₋₆ akylsulfinyl group, the C₁₋₆alkylsulfonyl group, the C₁₋₆ alkylcarbonyl group, the C₁₋₆alkoxycarbonyl group, the phenoxycarbonyl group, the C₁₋₆alkylcarbonyloxy group, the C₃₋₇ cycloalkyl group, the phenyl group, thephenoxy group, the phenylthio group, the phenylsulfinyl group, thephenylsulfonyl group, the benzoyl group, the benzoyloxy group, andbenzyloxy group may be substituted by the same substituent assubstituent for sadi C₁₋₆ alkyl group as each of Z₁, Z₁ ', and Z₁ ", orQ is a phenyl group which may be substituted by a halogen atom, ahydroxyl group, a mercapto group, a cyano group, a nitro group, a C₁₋₆akylsulfinyl group, a C₁₋₆ alkylsulfonyl group, a C₁₋₆ alky group, aC₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylcarbonyl group, aC₁₋₆ akoxycarbonyl group, or a C₁₋₆ alkylcarbonyloxy groupwherein eachof the C₁₋₆ alkyl group, the C₁₋₆ alkoxy group, the C₁₋₆ akylthio group,the C₁₋₆ alkylcarbonyl group, the C₁₋₆ alkoxycarbonyl group, and theC₁₋₆ alkylcarbonyloxy group may be substituted by teh same substitutentas substituent for said C₁₋₆ alkyl group as each of Z₁, Z₁ ', and Z₁ ",the total number of atoms of Q other than hydrogen atoms being 30 orless.
 50. A 6-O-substituted chartreusin derivative according to claim49, wherein each of R, R' and R" in Q is said C₁₋₁₁ alkanediyl group andthe total number of atoms of Q other than hydrogen atom is 15 or less.51. A 6-0-substituted chartreusin derivative according to claim 49,wherein Q is said C₁₋₁₁ alkyl group or said C₃₋₁₀ cycloalkyl group; andthe total number of atoms of Q other than hydrogen atom being 15 orless.